Isoindoline derivatives, pharmaceutical compositions containing them, and their use in therapy

ABSTRACT

The present invention relates to isoindoline derivatives of the formula (I) 
                         
or a physiologically tolerated salt thereof.
 
     The present invention also relates to pharmaceutical compositions comprising such isoindoline derivatives, and the use of such isoindoline derivatives for therapeutic purposes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/719,647, filed on Oct. 29, 2012 and U.S. Provisional PatentApplication No. 61/598,083, filed on Feb. 13, 2012, the contents of eachof which are herein fully incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention relates to isoindoline derivatives, pharmaceuticalcompositions comprising such isoindoline derivatives, and the use ofsuch isoindoline derivatives for therapeutic purposes. The isoindolinederivatives are GlyT1 inhibitors.

Dysfunction of glutamatergic pathways has been implicated in a number ofdisease states in the human central nervous system (CNS) including butnot limited to schizophrenia, cognitive deficits, dementia, Parkinsondisease, Alzheimer disease and bipolar disorder. A large number ofstudies in animal models lend support to the NMDA hypofunctionhypothesis of schizophrenia.

NMDA receptor function can be modulated by altering the availability ofthe co-agonist glycine. This approach has the critical advantage ofmaintaining activity-dependent activation of the NMDA receptor becausean increase in the synaptic concentration of glycine will not produce anactivation of NMDA receptors in the absence of glutamate. Since synapticglutamate levels are tightly maintained by high affinity transportmechanisms, an increased activation of the glycine site will onlyenhance the NMDA component of activated synapses.

Two specific glycine transporters, GlyT1 and GlyT2 have been identifiedand shown to belong to the Na/Cl-dependent family of neurotransmittertransporters which includes taurine, gamma-aminobutyric acid (GABA),proline, monoamines and orphan transporters. GlyT1 and GlyT2 have beenisolated from different species and shown to have only 50% identity atthe amino acid level. They also have a different pattern of expressionin mammalian central nervous system, with GlyT2 being expressed inspinal cord, brainstem and cerebellum and GlyT1 present in these regionsas well as forebrain areas such as cortex, hippocampus, septum andthalamus. At the cellular level, GlyT2 has been reported to be expressedby glycinergic nerve endings in rat spinal cord whereas GlyT1 appears tobe preferentially expressed by glial cells. These expression studieshave led to the suggestion that GlyT2 is predominantly responsible forglycine uptake at glycinergic synapses whereas GlyT1 is involved inmonitoring glycine concentration in the vicinity of NMDA receptorexpressing synapses. Recent functional studies in rat have shown thatblockade of GlyT1 with the potent inhibitor(N-[3-(4′-fluorophenyl)-3-(4′-phenylphenoxy)propyl])-sarcosine (NFPS)potentiates NMDA receptor activity and NMDA receptor-dependent long-termpotentiation in rat.

Molecular cloning has further revealed the existence of three variantsof GlyT1, termed GlyT-1a, GlyT-1b and GlyT-1c, each of which displays aunique distribution in the brain and peripheral tissues. The variantsarise by differential splicing and exon usage, and differ in theirN-terminal regions.

The physiological effects of GlyT1 in forebrain regions together withclinical reports showing the beneficial effects of GlyT1 inhibitorsarcosine in improving symptoms in schizophrenia patients suggest thatselective GlyT1 inhibitors represent a new class of antipsychotic drugs.

Glycine transporter inhibitors are already known in the art, forexample:

(see also Hashimoto K., Recent Patents on CNS Drug Discovery, 2006, 1,43-53; Harsing L. G. et al., Current Medicinal Chemistry, 2006, 13,1017-1044; Javitt D. C., Molecular Psychiatry (2004) 9, 984-997;Lindsley, C. W. et al., Current Topics in Medicinal Chemistry, 2006, 6,771-785; Lindsley C. W. et al., Current Topics in Medicinal Chemistry,2006, 6, 1883-1896).

It was one object of the present invention to provide further glycinetransporter inhibitors.

SUMMARY OF THE INVENTION

The present invention relates to isoindoline derivatives of the formula(I)

-   -   wherein

-   R is R¹-W-A¹-Q-Y-A²-X¹- or —CN;

-   R¹ is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl,    trialkylsilylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,    alkylaminoalkyl, dialkylaminoalkyl, alkylcarbonylaminoalkyl,    alkyloxycarbonylaminoalkyl, alkylaminocarbonylaminoalkyl,    dialkylaminocarbonylaminoalkyl, alkylsulfonylaminoalkyl, (optionally    substituted arylalkyl)aminoalkyl, optionally substituted arylalkyl,    optionally substituted heterocyclylalkyl, cycloalkyl, alkylcarbonyl,    alkoxycarbonyl, halogenated alkoxycarbonyl, aryloxycarbonyl,    aminocarbonyl, alkylaminocarbonyl, (halogenated alkyl)aminocarbonyl,    arylaminocarbonyl, alkenyl, alkynyl, optionally substituted aryl,    hydroxy, alkoxy, halogenated alkoxy, hydroxyalkoxy, alkoxyalkoxy,    aminoalkoxy, alkylaminoalkoxy, dialkylaminoalkoxy,    alkylcarbonylaminoalkoxy, arylcarbonylaminoalkoxy,    alkoxycarbonylaminoalkoxy, arylalkoxy, alkylsulfonylaminoalkoxy,    (halogenated alkyl)sulfonylaminoalkoxy, arylsulfonylaminoalkoxy,    (arylalkyl)sulfonylaminoalkoxy, heterocyclylsulfonylaminoalkoxy,    heterocyclylalkoxy, aryloxy, heterocyclyloxy, alkylthio, halogenated    alkylthio, alkylamino, (halogenated alkyl)amino, dialkylamino,    di-(halogenated alkyl)amino, alkylcarbonylamino, (halogenated    alkyl)carbonylamino, arylcarbonylamino, alkylsulfonylamino,    (halogenated alkyl)sulfonylamino, arylsulfonylamino or optionally    substituted heterocyclyl;

-   W is —NR⁸— or a bond;

-   A¹ is optionally substituted alkylene or a bond;

-   Q is —S(O)₂— or —C(O)—;

-   Y is —NR⁹— or a bond;

-   A² is optionally substituted alkylene, alkylene-CO—, —CO-alkylene,    alkylene-O-alkylene, alkylene-NR¹⁰-alkylene, optionally substituted    alkenylene, optionally substituted alkynylene, optionally    substituted arylene, optionally substituted heteroarylene or a bond;

-   X¹ is —O—, —NR¹¹, —S—, optionally substituted alkylene, optionally    substituted alkenylene, optionally substituted alkynylene;

-   R² is hydrogen, halogen, alkyl, halogenated alkyl, hydroxyalkyl,    —CN, alkenyl, alkynyl, optionally substituted aryl, hydroxy, alkoxy,    halogenated alkoxy, alkoxycarbonyl, alkenyloxy, arylalkoxy,    alkylcarbonyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl,    aminosulfonyl, amino, alkylamino, alkenylamino, nitro or optionally    substituted heterocyclyl, or two radicals R² together with the ring    atoms to which they are bound form a 5- or 6-membered ring;

-   R³ is hydrogen, halogen, alkyl or alkoxy, or two radicals R³    together with the carbon atom to which they are attached form a    carbonyl group;

-   R⁴ is hydrogen, alkyl, cycloalkylalkyl, halogenated alkyl,    hydroxyalkyl, alkoxyalkyl, aminoalkyl, CH₂CN, arylalkyl, cycloalkyl,    —CHO, alkylcarbonyl, (halogenated alkyl)carbonyl, arylcarbonyl,    alkoxycarbonyl, aryloxycarbonyl, alkylaminocarbonyl, alkenyl,    —C(═NH)NH₂, —C(═NH)NHCN, alkylsulfonyl, arylsulfonyl, amino, —NO or    heterocyclyl;

-   X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond;

-   X³ is —O—, —NR⁷—, —S—, >CR^(13a)R^(13b) or a bond;

-   R⁵ is optionally substituted aryl, optionally substituted cycloalkyl    or optionally substituted heterocyclyl;

-   R⁶ is hydrogen or alkyl;

-   R⁷ is hydrogen or alkyl;

-   R⁸ is hydrogen or alkyl;

-   R⁹ is hydrogen, alkyl, cycloalkyl, aminoalkyl, optionally    substituted arylalkyl or heterocyclyl, or

-   R⁹, R¹    -   together are alkylene, or

-   R⁹ is alkylene that is bound to a carbon atom in A² and A² is    alkylene or to a carbon atom in X¹ and X¹ is alkylene;

-   R¹⁰ is hydrogen, alkyl or alkylsulfonyl;

-   R¹¹ is hydrogen or alkyl, or

-   R⁹, R¹¹    -   together are alkylene;

-   R^(12a) is hydrogen, optionally substituted alkyl, alkylaminoalkyl,    dialkylaminoalkyl, heterocyclyl-alkyl, optionally substituted aryl    or hydroxy;

-   R^(12b) is hydrogen or alkyl, or

-   R^(12a), R^(12b)    -   together are carbonyl or optionally substituted alkylene,        wherein one —CH₂— of alkylene may be replaced by an oxygen atom        or —NR¹⁴—;

-   R^(13a) is hydrogen, optionally substituted alkyl, alkylaminoalkyl,    dialkylaminoalkyl, heterocyclyl-alkyl, optionally substituted aryl    or hydroxy;

-   R^(13b) is hydrogen or alkyl, or

-   R^(13a), R^(13b),    -   together are carbonyl or optionally substituted alkylene,        wherein one —CH₂— of alkylene may be replaced by an oxygen atom        or —NR¹⁵—;

-   R¹⁴ is hydrogen or alkyl; and

-   R¹⁵ is hydrogen or alkyl,    or a physiologically tolerated salt thereof.

Thus, the present invention relates to isoindoline derivatives havingthe formula (Ia)

wherein R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴, X², X³, R⁵ are as definedherein.

Further, the present invention relates to isoindoline derivatives offormula (I) wherein R is —CN, i.e. isoindoline derivatives having theformula (Ib)

wherein R², R³, R⁴, X², X³, R⁵ are as defined herein.

Said compounds of formula (I), i.e., the isoindoline derivatives offormula (I) and their physiologically tolerated salts, are glycinetransporter inhibitors and thus useful as pharmaceuticals. The compoundsof formula (I) display good to moderate metabolic stability.

The present invention thus further relates to the compounds of formula(I) for use in therapy.

The present invention also relates to pharmaceutical compositions whichcomprise a carrier and a compound of formula (I).

In particular, said compounds, i.e., the isoindoline derivatives andtheir physiologically tolerated salts, are inhibitors of the glycinetransporter GlyT1.

The present invention thus further relates to the compounds of formula(I) for use in inhibiting the glycine transporter.

The present invention also relates to the use of the compounds offormula (I) in the manufacture of a medicament for inhibiting theglycine transporter GlyT1 and corresponding methods of inhibiting theglycine transporter GlyT1.

Glycine transport inhibitors and in particular inhibitors of the glycinetransporter GlyT1 are known to be useful in treating a variety ofneurologic and psychiatric disorders.

The present invention thus further relates to the compounds of formula(I) for use in treating a neurologic or psychiatric disorder.

The present invention further relates to the compounds of formula (I)for use in treating pain.

The present invention also relates to the use of the compounds offormula (I) in the manufacture of a medicament for treating a neurologicor psychiatric disorder and corresponding methods of treating saiddisorders. The present invention also relates to the use of thecompounds of formula (I) in the manufacture of a medicament for treatingpain and corresponding methods of treating pain.

The present invention further relates to isoindolines derivatives offormula (II):

wherein L is an amino-protecting group, Y is NR⁹, and A², X¹, R², R³,R⁴, X², X³, R⁵ are as defined herein.

DETAILED DESCRIPTION OF THE INVENTION

Provided that the isoindoline derivatives of the formula (I) of a givenconstitution may exist in different spatial arrangements, for example ifthey possess one or more centers of asymmetry, polysubstituted rings ordouble bonds, or as different tautomers, it is also possible to useenantiomeric mixtures, in particular racemates, diastereomeric mixturesand tautomeric mixtures, preferably, however, the respective essentiallypure enantiomers, diastereomers and tautomers of the compounds offormula (I) and/or of their salts.

According to one embodiment, an enantiomer of the isoindolinederivatives of the present invention has the following formula:

wherein R, R², R³, R⁴, X², X³, R⁵ are as defined herein.

According to another embodiment, an enantiomer of the isoindolinederivatives of the present invention has the following formula:

wherein R, R², R³, R⁴, X², X³, R⁵ are as defined herein.

The physiologically tolerated salts of the isoindoline derivatives ofthe formula (I) are especially acid addition salts with physiologicallytolerated acids. Examples of suitable physiologically tolerated organicand inorganic acids are hydrochloric acid, hydrobromic acid, phosphoricacid, sulfuric acid, C₁-C₄-alkylsulfonic acids, such as methanesulfonicacid, cycloaliphatic sulfonic acids, such as S-(+)-10-camphor sulfonicacid, aromatic sulfonic acids, such as benzenesulfonic acid andtoluenesulfonic acid, di- and tricarboxylic acids and hydroxycarboxylicacids having 2 to 10 carbon atoms, such as oxalic acid, malonic acid,maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid,glycolic acid, adipic acid and benzoic acid. Other utilizable acids aredescribed, e.g., in Fortschritte der Arzneimittelforschung [Advances indrug research], Volume 10, pages 224 ff., Birkhäuser Verlag, Basel andStuttgart, 1966. The physiologically tolerated salts of the isoindolinederivatives also include salts of a physiologically tolerated anion withan isoindoline derivatives wherein one or more than one nitrogen atom isquaternized, e.g. with an alkyl residue (e.g. methyl or ethyl).

The present invention moreover relates to compounds of formula (I) asdefined herein, wherein at least one of the atoms has been replaced byits stable, non-radioactive isotope (e.g., hydrogen by deuterium, ¹²C by¹³C, ¹⁴N by ¹⁵N, ¹⁶O by ¹⁸O) and preferably wherein at least onehydrogen atom has been replaced by a deuterium atom.

Of course, such compounds contain more of the respective isotope thanthis naturally occurs and thus is anyway present in the compounds (I).

Stable isotopes (e.g., deuterium, ¹³C, ¹⁵N, ¹⁸O) are nonradioactiveisotopes which contain one or more additional neutron than the normallyabundant isotope of the respective atom. Deuterated compounds have beenused in pharmaceutical research to investigate the in vivo metabolicfate of the compounds by evaluation of the mechanism of action andmetabolic pathway of the non-deuterated parent compound (Blake et al. J.Pharm. Sci 64, 3, 367-391 (1975)). Such metabolic studies are importantin the design of safe, effective therapeutic drugs, either because thein vivo active compound administered to the patient or because themetabolites produced from the parent compound prove to be toxic orcarcinogenic (Foster et al., Advances in Drug Research Vol. 14, pp.2-36, Academic press, London, 1985; Kato et al., J. Labelled Comp.Radiopharmaceut., 36(10):927-932 (1995); Kushner et al., Can. J.Physiol. Pharmacol., 77, 79-88 (1999).

Incorporation of a heavy atom particularly substitution of deuterium forhydrogen, can give rise to an isotope effect that could alter thepharmacokinetics of the drug. This effect is usually insignificant ifthe label is placed at a metabolically inert position of the molecule.

Stable isotope labeling of a drug can alter its physico-chemicalproperties such as pKa and lipid solubility. These changes may influencethe fate of the drug at different steps along its passage through thebody. Absorption, distribution, metabolism or excretion can be changed.Absorption and distribution are processes that depend primarily on themolecular size and the lipophilicity of the substance. These effects andalterations can affect the pharmacodynamic response of the drug moleculeif the isotopic substitution affects a region involved in aligand-receptor interaction.

Drug metabolism can give rise to large isotopic effect if the breakingof a chemical bond to a deuterium atom is the rate limiting step in theprocess. While some of the physical properties of a stableisotope-labeled molecule are different from those of the unlabeled one,the chemical and biological properties are the same, with one importantexception: because of the increased mass of the heavy isotope, any bondinvolving the heavy isotope and another atom will be stronger than thesame bond between the light isotope and that atom. In any reaction inwhich the breaking of this bond is the rate limiting step, the reactionwill proceed slower for the molecule with the heavy isotope due to“kinetic isotope effect”. A reaction involving breaking a C-D bond canbe up to 700 percent slower than a similar reaction involving breaking aC—H bond. If the C-D bond is not involved in any of the steps leading tothe metabolite, there may not be any effect to alter the behavior of thedrug. If a deuterium is placed at a site involved in the metabolism of adrug, an isotope effect will be observed only if breaking of the C-Dbond is the rate limiting step. There is evidence to suggest thatwhenever cleavage of an aliphatic C—H bond occurs, usually by oxidationcatalyzed by a mixed-function oxidase, replacement of the hydrogen bydeuterium will lead to observable isotope effect. It is also importantto understand that the incorporation of deuterium at the site ofmetabolism slows its rate to the point where another metabolite producedby attack at a carbon atom not substituted by deuterium becomes themajor pathway a process called “metabolic switching”.

Deuterium tracers, such as deuterium-labeled drugs and doses, in somecases repeatedly, of thousands of milligrams of deuterated water, arealso used in healthy humans of all ages, including neonates and pregnantwomen, without reported incident (e.g. Pons G and Rey E, Pediatrics 1999104: 633; Coward W A et al., Lancet 1979 7: 13; Schwarcz H P, Control.Clin. Trials 1984 5(4 Suppl): 573; Rodewald L E et al., J. Pediatr. 1989114: 885; Butte N F et al. Br. J. Nutr. 1991 65: 3; MacLennan A H et al.Am. J. Obstet. Gynecol. 1981 139: 948). Thus, it is clear that anydeuterium released, for instance, during the metabolism of compounds ofthis invention poses no health risk.

The weight percentage of hydrogen in a mammal (approximately 9%) andnatural abundance of deuterium (approximately 0.015%) indicates that a70 kg human normally contains nearly a gram of deuterium. Furthermore,replacement of up to about 15% of normal hydrogen with deuterium hasbeen effected and maintained for a period of days to weeks in mammals,including rodents and dogs, with minimal observed adverse effects(Czajka D M and Finkel A J, Ann. N.Y. Acad. Sci. 1960 84: 770; Thomson JF, Ann. New York Acad. Sci. 1960 84: 736; Czakja D M et al., Am. J.Physiol. 1961 201: 357). Higher deuterium concentrations, usually inexcess of 20%, can be toxic in animals. However, acute replacement of ashigh as 15%-23% of the hydrogen in humans' fluids with deuterium wasfound not to cause toxicity (Blagojevic N et al. in “Dosimetry &Treatment Planning for Neutron Capture Therapy”, Zamenhof R, Solares Gand Harling O Eds. 1994. Advanced Medical Publishing, Madison Wis. pp.125-134; Diabetes Metab. 23: 251 (1997)).

Increasing the amount of deuterium present in a compound above itsnatural abundance is called enrichment or deuterium-enrichment. Examplesof the amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71,75, 79, 84, 88, 92, 96, to about 100 mol %.

The hydrogens present on a particular organic compound have differentcapacities for exchange with deuterium. Certain hydrogen atoms areeasily exchangeable under physiological conditions and, if replaced bydeuterium atoms, it is expected that they will readily exchange forprotons after administration to a patient. Certain hydrogen atoms may beexchanged for deuterium atoms by the action of a deuteric acid such asD₂SO₄/D₂O. Alternatively, deuterium atoms may be incorporated in variouscombinations during the synthesis of compounds of the invention. Certainhydrogen atoms are not easily exchangeable for deuterium atoms. However,deuterium atoms at the remaining positions may be incorporated by theuse of deuterated starting materials or intermediates during theconstruction of compounds of the invention.

Deuterated and deuterium-enriched compounds of the invention can beprepared by using known methods described in the literature. Suchmethods can be carried out utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure. Relevant procedures and intermediates are disclosed,for instance in Lizondo, J et al., Drugs Fut, 21(11), 1116 (1996);Brickner, S J et al., J Med Chem, 39(3), 673 (1996); Mallesham, B etal., Org Lett, 5(7), 963 (2003); PCT publications WO1997010223,WO2005099353, WO1995007271, WO2006008754; U.S. Pat. Nos. 7,538,189;7,534,814; 7531685; 7528131; 7521421; 7514068; 7511013; and US PatentApplication Publication Nos. 20090137457; 20090131485; 20090131363;20090118238; 20090111840; 20090105338; 20090105307; 20090105147;20090093422; 20090088416; 20090082471, the methods are herebyincorporated by reference.

The organic moieties mentioned in the above definitions of the variablesare—like the term halogen—collective terms for individual listings ofthe individual group members. The prefix C_(n)-C_(m) indicates in eachcase the possible number of carbon atoms in the group.

Unless indicated otherwise, the term “substituted” means that a radicalis substituted with 1, 2 or 3, especially 1, substituent which are inparticular selected from the group consisting of halogen, C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, C₃-C₁₂-heterocyclyl-alkyl,C₁-C₄-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl, C₁-C₄-alkenyl, OH, SH, CN,CF₃, O—CF₃, COOH, O—CH₂—COOH, C₁-C₆-alkoxy, C₁-C₆-alkylthio,C₃-C₇-cycloalkyl, COO—C₁-C₆-alkyl, CONH₂, CONH—C₁-C₆-alkyl,SO₂NH—C₁-C₆-alkyl, CON—(C₁-C₆-alkyl)₂, SO₂N—(C₁-C₆-alkyl)₂, NH₂,NH—C₁-C₆-alkyl, N—(C₁-C₆-alkyl)₂, NH—(C₁-C₄-alkyl-C₆-C₁₂-aryl),NH—CO—C₁-C₆-alkyl, NH—SO₂—C₁-C₆-alkyl, SO₂—C₁-C₆-alkyl, C₆-C₁₂-aryl,O—C₆-C₁₂-aryl, O—CH₂—C₆-C₁₂-aryl, CONH—C₆-C₁₂-aryl, SO₂NH—C₆-C₁₂-aryl,CONH—C₃-C₁₂-heterocyclyl, SO₂NH—C₃-C₁₂-heterocyclyl, SO₂—C₆-C₁₂-aryl,NH—SO₂—C₆-C₁₂-aryl, NH—CO—C₆-C₁₂-aryl, NH—SO₂—C₃-C₁₂-heterocyclyl,NH—CO—C₃-C₁₂-heterocyclyl and C₃-C₁₂-heterocyclyl, wherein aryl andheterocyclyl in turn may be unsubstituted or substituted with 1, 2 or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

The term halogen denotes in each case fluorine, bromine, chlorine oriodine, in particular fluorine or chlorine.

C₁-C₄-Alkyl is a straight-chain or branched alkyl group having from 1 to4 carbon atoms. Examples of an alkyl group are methyl, C₂-C₄-alkyl suchas ethyl, n-propyl, iso-propyl, n-butyl, 2-butyl, iso-butyl ortert-butyl. C₁-C₂-Alkyl is methyl or ethyl, C₁-C₃-alkyl is additionallyn-propyl or isopropyl.

C₁-C₆-Alkyl is a straight-chain or branched alkyl group having from 1 to6 carbon atoms. Examples include methyl, C₂-C₄-alkyl as mentioned hereinand also pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl,2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1,1-dimethylpropyl,1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl,4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

Halogenated C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, wherein at least one, e.g. 1, 2, 3, 4 orall of the hydrogen atoms are replaced by 1, 2, 3, 4 or a correspondingnumber of identical or different halogen atoms, such as inhalogenomethyl, dihalogenomethyl, trihalogenomethyl,(R)-1-halogenoethyl, (S)-1-halogenoethyl, 2-halogenoethyl,1,1-dihalogenoethyl, 2,2-dihalogenoethyl, 2,2,2-trihalogenoethyl,(R)-1-halogenopropyl, (S)-1-halogenopropyl, 2-halogenopropyl,3-halogenopropyl, 1,1-dihalogenopropyl, 2,2-dihalogenopropyl,3,3-dihalogenopropyl, 3,3,3-trihalogenopropyl,(R)-2-halogeno-1-methylethyl, (S)-2-halogeno-1-methylethyl,(R)-2,2-dihalogeno-1-methylethyl, (S)-2,2-dihalogeno-1-methylethyl,(R)-1,2-dihalogeno-1-methylethyl, (S)-1,2-dihalogeno-1-methylethyl,(R)-2,2,2-trihalogeno-1-methylethyl,(S)-2,2,2-trihalogeno-1-methylethyl, 2-halogeno-1-(halogenomethyl)ethyl,1-(dihalogenomethyl)-2,2-dihalogenoethyl, (R)-1-halogenobutyl,(S)-1-halogenobutyl, 2-halogenobutyl, 3-halogenobutyl, 4-halogenobutyl,1,1-dihalogenobutyl, 2,2-dihalogenobutyl, 3,3-dihalogenobutyl,4,4-dihalogenobutyl, 4,4,4-trihalogenobutyl, etc. Particular examplesinclude the fluorinated C₁-C₄ alkyl groups as defined, such astrifluoromethyl.

C₆-C₁₂-Aryl-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by C₆-C₁₂-aryl, such as in benzyl.

Hydroxy-C₁-C₄-alkyl is a straight-chain or branched alkyl group having 1to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or2 carbon atoms, wherein one or two hydrogen atoms are replaced by one ortwo hydroxyl groups, such as in hydroxymethyl, (R)-1-hydroxyethyl,(S)-1-hydroxyethyl, 2-hydroxyethyl, (R)-1-hydroxypropyl,(S)-1-hydroxypropyl, 2-hydroxypropyl, 3-hydroxypropyl,(R)-2-hydroxy-1-methylethyl, (S)-2-hydroxy-1-methylethyl,2-hydroxy-1-(hydroxymethyl)ethyl, (R)-1-hydroxybutyl,(S)-1-hydroxybutyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl.

C₁-C₆-Alkoxy-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, wherein one or two hydrogen atoms arereplaced by one or two alkoxy groups having 1 to 6, preferably 1 to 4,in particular 1 or 2 carbon atoms, such as in methoxymethyl,(R)-1-methoxyethyl, (S)-1-methoxyethyl, 2-methoxyethyl,(R)-1-methoxypropyl, (S)-1-methoxypropyl, 2-methoxypropyl,3-methoxypropyl, (R)-2-methoxy-1-methylethyl,(S)-2-methoxy-1-methylethyl, 2-methoxy-1-(methoxymethyl)ethyl,(R)-1-methoxybutyl, (S)-1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl,4-methoxybutyl, ethoxymethyl, (R)-1-ethoxyethyl, (S)-1-ethoxyethyl,2-ethoxyethyl, (R)-1-ethoxypropyl, (S)-1-ethoxypropyl, 2-ethoxypropyl,3-ethoxypropyl, (R)-2-ethoxy-1-methylethyl, (S)-2-ethoxy-1-methylethyl,2-ethoxy-1-(ethoxymethyl)ethyl, (R)-1-ethoxybutyl, (S)-1-ethoxybutyl,2-ethoxybutyl, 3-ethoxybutyl, 4-ethoxybutyl.

Amino-C₁-C₄-alkyl is a straight-chain or branched alkyl group having 1to 4 carbon atoms, preferably 1 to 3 carbon atoms, more preferably 1 or2 carbon atoms, in particular 1 or two carbon atoms, wherein onehydrogen atom is replaced by an amino group, such as in aminomethyl,2-aminoethyl.

C₁-C₆-Alkylamino-C₁-C₄-alkyl is a straight-chain or branched alkyl grouphaving 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by a C₁-C₆-alkylamino group, inparticular by a C₁-C₄-alkylamino group, such as in methylaminomethyl,ethylaminomethyl, n-propylaminomethyl, iso-propylaminomethyl,n-butylaminomethyl, 2-butylaminomethyl, iso-butylaminomethyl ortert-butylaminomethyl.

Di-C₁-C₆-Alkylamino-C₁-C₄-alkyl is a straight-chain or branched alkylgroup having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by a di-C₁-C₆-Alkylamino group, inparticular by a di-C₁-C₄-alkylamino group, such as indimethylaminomethyl.

C₁-C₆-Alkylcarbonylamino-C₁-C₄-alkyl is a straight-chain or branchedalkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms,more preferably 1 or 2 carbon atoms, in particular 1 or two carbonatoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylcarbonylamino group, in particular by aC₁-C₄-alkylcarbonylamino group, such as in methylcarbonylaminomethyl,ethylcarbonylaminomethyl, n-propylcarbonylaminomethyl,iso-propylcarbonylaminomethyl, n-butylcarbonylaminomethyl,2-butylcarbonylaminomethyl, iso-butylcarbonylaminomethyl ortertbutylcarbonylaminomethyl.

C₁-C₆-Alkylaminocarbonylamino-C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylaminocarbonylamino group, in particular by aC₁-C₄-alkylaminocarbonylamino group, such as inmethylaminocarbonylaminomethyl, ethylaminocarbonylaminomethyl,n-propylaminocarbonylaminomethyl, iso-propylaminocarbonylaminomethyl,n-butylaminocarbonylaminomethyl, 2-butylaminocarbonylaminomethyl,iso-butylaminocarbonylaminomethyl or tert-butylaminocarbonylaminomethyl.

Di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by adi-C₁-C₆-alkylaminocarbonylamino group, in particular by adi-C₁-C₄-alkylaminocarbonylamino group, such as indimethylaminocarbonylaminomethyl, dimethylaminocarbonylaminoethyl,dimethylaminocarbonylamino-propyl.

C₁-C₆-Alkylsulfonylamino-C₁-C₄-alkyl is a straight-chain or branchedalkyl group having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms,more preferably 1 or 2 carbon atoms, in particular 1 or two carbonatoms, wherein one hydrogen atom is replaced by aC₁-C₆-alkylsulfonylamino group, in particular by aC₁-C₄-alkylsulfonylamino group, such as in methylsulfonylaminomethyl,ethylsulfonylaminomethyl, n-propylsulfonylaminomethyl,isopropylsulfonylaminomethyl, n-butylsulfonylaminomethyl,2-butylsulfonylaminomethyl, isobutylsulfonylaminomethyl ortert-butylsulfonylaminomethyl.

(C₆-C₁₂-Aryl-C₁-C₆-alkyl)amino-C₁-C₄ alkyl is a straight-chain orbranched alkyl group having 1 to 4 carbon atoms, preferably 1 to 3carbon atoms, more preferably 1 or 2 carbon atoms, in particular 1 ortwo carbon atoms, wherein one hydrogen atom is replaced by a(C₆-C₁₂-aryl-C₁-C₆-alkyl)amino group, in particular a(C₆-C₁₂-aryl-C₁-C₂-alkyl)amino group, such as in benzylaminomethyl.

C₃-C₁₂-Heterocyclyl-C₁-C₄-alkyl is a straight-chain or branched alkylgroup having 1 to 4 carbon atoms, preferably 1 to 3 carbon atoms, morepreferably 1 or 2 carbon atoms, in particular 1 or two carbon atoms,wherein one hydrogen atom is replaced by C₃-C₁₂-heterocyclyl, such as inN-pyrrolidinylmethyl, N-piperidinylmethyl, N-morpholinylmethyl.

C₃-C₁₂-Cycloalkyl is a cycloaliphatic radical having from 3 to 12 carbonatoms. In particular, 3 to 6 carbon atoms form the cyclic structure,such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The cyclicstructure may be unsubstituted or may carry 1, 2, 3 or 4 C₁-C₄ alkylradicals, preferably one or more methyl radicals.

Carbonyl is >C═O.

C₁-C₆-Alkylcarbonyl is a radical of the formula R—C(O)—, wherein R is analkyl radical having from 1 to 6, preferably from 1 to 4, in particular1 or 2 carbon atoms as defined herein. Examples include acetyl,propionyl, n-butyryl, 2-methylpropionyl, pivaloyl.

Halogenated C₁-C₆-alkylcarbonyl is C₁-C₆-alkylcarbonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms. Examples include fluoromethylcarbonyl,difluoromethylcarbonyl, trifluoromethylcarbonyl. Further examples are1,1,1-trifluoroeth-2-ylcarbonyl, 1,1,1-trifluoroprop-3-ylcarbonyl.

C₆-C₁₂-Arylcarbonyl is a radical of the formula R—C(O)—, wherein R is anaryl radical having from 6 to 12 carbon atoms as defined herein.Examples include benzoyl.

C₁-C₆-Alkoxycarbonyl is a radical of the formula R—O—C(O)—, wherein R isan alkyl radical having from 1 to 6, preferably from 1 to 4, inparticular 1 or 2 carbon atoms as defined herein. Examples includemethoxycarbonyl and tert-butyloxycarbonyl.

Halogenated C₁-C₆-alkoxycarbonyl is a C₁-C₆-alkoxycarbonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₆-C₁₂-Aryloxycarbonyl is a radical of the formula R—O—C(O)—, wherein Ris an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenoxycarbonyl.

Cyano is —C≡N.

Aminocarbonyl is NH₂C(O)—.

C₁-C₆-Alkylaminocarbonyl is a radical of the formula R—NH—C(O)—, whereinR is an alkyl radical having from 1 to 6, preferably from 1 to 4, inparticular 1 or 2 carbon atoms as defined herein. Examples includemethylaminocarbonyl.

(Halogenated C₁-C₄-alkyl)aminocarbonyl is a C₁-C₄-alkylaminocarbonyl asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different hydrogen atoms.

C₆-C₁₂-Arylaminocarbonyl is a radical of the formula R—NH—C(O)—, whereinR is an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylaminocarbonyl.

C₂-C₆-Alkenyl is a singly unsaturated hydrocarbon radical having 2, 3,4, 5 or 6 carbon atoms, e.g. vinyl, allyl(2-propen-1-yl), 1-propen-1-yl,2-propen-2-yl, methallyl(2-methylprop-2-en-1-yl) and the like.C₃-C₅-Alkenyl is, in particular, allyl, 1-methylprop-2-en-1-yl,2-buten-1-yl, 3-buten-1-yl, methallyl, 2-penten-1-yl, 3-penten-1-yl,4-penten-1-yl, 1-methylbut-2-en-1-yl or 2-ethylprop-2-en-1-yl.

C₂-C₆-Alkynyl is a singly unsaturated hydrocarbon radical having 2, 3,4, 5 or 6 carbon atoms, e.g. ethynyl, 2-propyn-1-yl, 1-propyn-1-yl,2-propyn-2-yl and the like. C₃-C₅-Alkynyl is, in particular,2-propyn-1-yl, 2-butyn-1-yl, 3-butyn-1-yl, 2-pentyn-1-yl, 3-pentyn-1-yl,4-pentyn-1-yl.

C₁-C₄-Alkylene is straight-chain or branched alkylene group having from1 to 4 carbon atoms. Examples include methylene and ethylene. A furtherexample is propylene.

C₂-C₄-Alkenylene is straight-chain or branched alkenylene group havingfrom 2 to 4 carbon atoms.

C₂-C₄-Alkynylene is straight-chain or branched alkynylene group havingfrom 2 to 4 carbon atoms. Examples include propynylene.

C₆-C₁₂-Aryl is a 6- to 12-membered, in particular 6- to 10-membered,aromatic cyclic radical. Examples include phenyl and naphthyl.

C₃-C₁₂-Arylene is an aryl diradical. Examples include phen-1,4-ylene andphen-1,3-ylene.

Hydroxy is —OH.

C₁-C₆-Alkoxy is a radical of the formula R—O—, wherein R is astraight-chain or branched alkyl group having from 1 to 6, in particular1 to 4 carbon atoms. Examples include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, 2-butoxy, iso-butoxy(2-methylpropoxy),tert.-butoxy pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy,2,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 1-methylpentyloxy, 2-methylpentyloxy,3-methylpentyloxy, 4-methylpentyloxy, 1,1-dimethylbutyloxy,1,2-dimethylbutyloxy, 1,3-dimethylbutyloxy, 2,2-dimethylbutyloxy,2,3-dimethylbutyloxy, 3,3-dimethylbutyloxy, 1-ethylbutyloxy,2-ethylbutyloxy, 1,1,2-trimethylpropoxy, 1,2,2-trimethylpropoxy,1-ethyl-1-methylpropoxy and 1-ethyl-2-methylpropoxy.

Halogenated C₁-C₆-alkoxy is a straight-chain or branched alkoxy grouphaving from 1 to 6, preferably from 1 to 4, in particular 1 or 2 carbonatoms, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms, such as in halogenomethoxy,dihalogenomethoxy, trihalogenomethoxy, (R)-1-halogenoethoxy,(S)-1-halogenoethoxy, 2-halogenoethoxy, 1,1-dihalogenoethoxy,2,2-dihalogenoethoxy, 2,2,2-trihalogenoethoxy, (R)-1-halogenopropoxy,(S)-1-halogenopropoxy, 2-halogenopropoxy, 3-halogenopropoxy,1,1-dihalogenopropoxy, 2,2-dihalogenopropoxy, 3,3-dihalogenopropoxy,3,3,3-trihalogenopropoxy, (R)-2-halogeno-1-methylethoxy,(S)-2-halogeno-1-methylethoxy, (R)-2,2-dihalogeno-1-methylethoxy,(S)-2,2-dihalogeno-1-methylethoxy, (R)-1,2-dihalogeno-1-methylethoxy,(S)-1,2-dihalogeno-1-methylethoxy, (R)-2,2,2-trihalogeno-1-methylethoxy,(S)-2,2,2-trihalogeno-1-methylethoxy,2-halogeno-1-(halogenomethyl)ethoxy,1-(dihalogenomethyl)-2,2-dihalogenoethoxy, (R)-1-halogenobutoxy,(S)-1-halogenobutoxy, 2-halogenobutoxy, 3-halogenobutoxy,4-halogenobutoxy, 1,1-dihalogenobutoxy, 2,2-dihalogenobutoxy,3,3-dihalogenobutoxy, 4,4-dihalogenobutoxy, 4,4,4-trihalogenobutoxy,etc. Particular examples include the fluorinated C₁-C₄ alkoxy groups asdefined, such as trifluoromethoxy.

C₁-C₆-Hydroxyalkoxy is an alkoxy radical having from 1 to 6, preferablyfrom 1 to 4 carbon atoms as defined herein, wherein one or two hydrogenatoms are replaced by hydroxy. Examples include 2-hydroxyethoxy,3-hydroxypropoxy, 2-hydroxypropoxy, 1-methyl-2-hydroxyethoxy and thelike.

C₁-C₆-Alkoxy-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4 carbonatoms, preferably 1 or 2 carbon atoms as defined herein, wherein one ortwo hydrogen atoms are replaced by one or two alkoxy radicals havingfrom 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.Examples include methoxymethoxy, 2-methoxyethoxy, 1-methoxyethoxy,3-methoxypropoxy, 2-methoxypropoxy, 1-methyl-1-methoxyethoxy,ethoxymethoxy, 2-ethoxyethoxy, 1-ethoxyethoxy, 3-ethoxypropoxy,2-ethoxypropoxy, 1-methyl-1-ethoxyethoxy and the like.

Amino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4, preferably 1or 2 carbon atoms as defined herein, wherein one hydrogen atom isreplaced by an amino group. Examples include 2-aminoethoxy.

C₁-C₆-Alkylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4,preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogenatom is replaced by an alkylamino group having from 1 to 6, preferablyfrom 1 to 4 carbon atoms as defined herein. Examples includemethylaminomethoxy, ethylaminomethoxy, n-propylaminomethoxy,isopropylaminomethoxy, n-butylaminomethoxy, 2-butylaminomethoxy,isobutylaminomethoxy, tert-butylaminomethoxy, 2-(methylamino)ethoxy,2-(ethylamino)ethoxy, 2-(n-propylamino)ethoxy,2-(iso-propylamino)ethoxy, 2-(n-butylamino)ethoxy,2-(2-butylamino)ethoxy, 2-(iso-butylamino)ethoxy,2-(tertbutylamino)ethoxy.

Di-C₁-C₆-alkylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1 to4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a dialkylamino group having from 1 to 6,preferably from 1 to 4 carbon atoms as defined herein. Examples includedimethylaminomethoxy, diethylaminomethoxy, N-methyl-N-ethylamino)ethoxy,2-(dimethylamino)ethoxy, 2-(diethylamino)ethoxy,2-(N-methyl-N-ethylamino)ethoxy.

C₁-C₆-Alkylcarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkylcarbonylamino group wherein thealkyl group has from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylcarbonylaminomethoxy,ethylcarbonylaminomethoxy, n-propylcarbonylaminomethoxy,isopropylcarbonylaminomethoxy, n-butylcarbonylaminomethoxy,2-butylcarbonylaminomethoxy, iso-butylcarbonylaminomethoxy,tert-butylcarbonylaminomethoxy, 2-(methylcarbonylamino)ethoxy,2-(ethylcarbonylamino)ethoxy, 2-(n-propylcarbonylamino)ethoxy,2-(iso-propylcarbonylamino)ethoxy, 2-(n-butylcarbonylamino)ethoxy,2-(2-butylcarbonylamino)ethoxy, 2-(iso-butylcarbonyl-amino)ethoxy,2-(tert-butylcarbonylamino)ethoxy.

C₆-C₁₂-Arylcarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₆-C₁₂-arylcarbonylamino group as definedherein. Examples include 2-(benzoylamino)ethoxy.

C₁-C₆-Alkoxycarbonylamino-C₁-C₄-alkoxy is an alkoxy radical having from1 to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkoxycarbonylamino group wherein thealkoxy group has from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methoxycarbonylaminomethoxy,ethoxycarbonylaminomethoxy, n-propoxycarbonylaminomethoxy,isopropoxycarbonylaminomethoxy, n-butoxycarbonylaminomethoxy,2-butoxycarbonylaminomethoxy, iso-butoxycarbonylaminomethoxy,tertbutoxycarbonylaminomethoxy, 2-(methoxycarbonylamino)ethoxy,2-(ethoxycarbonylamino)ethoxy, 2-(n-propoxycarbonylamino)ethoxy,2-(iso-propoxycarbonylamino)ethoxy, 2-(n-butoxycarbonylamino)ethoxy,2-(2-butoxycarbonylamino)ethoxy, 2-(isobutoxycarbonylamino)ethoxy,2-(tert-butoxycarbonylamino)ethoxy.

C₂-C₆-Alkenyloxy is a radical of the formula R—O—, wherein R is astraight-chain or branched alkenyl group having from 2 to 6, inparticular 2 to 4 carbon atoms. Examples include vinyloxy,allyloxy(2-propen-1-yloxy), 1-propen-1-yloxy, 2-propen-2-yloxy,methallyloxy(2-methylprop-2-en-1-yloxy) and the like. C₃-C₅-Alkenyloxyis, in particular, allyloxy, 1-methylprop-2-en-1-yloxy, 2-buten-1-yloxy,3-buten-1-yloxy, methallyloxy, 2-penten-1-yloxy, 3-penten-1-yloxy,4-penten-1-yloxy, 1-methylbut-2-en-1-yloxy or 2-ethylprop-2-en-1-yloxy.

C₆-C₁₂-Aryl-C₁-C₄-alkoxy is an alkoxy radical having from 1 to 4,preferably 1 or 2 carbon atoms as defined herein, wherein one hydrogenatom is replaced by a C₆-C₁₂-aryl group as defined herein. Examplesinclude benzyloxy.

C₁-C₆-Alkylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by an alkylsulfonylamino group having from 1to 6, preferably from 1 to 4 carbon atoms as defined herein. Examplesinclude 2-(methylsulfonylamino)ethoxy, 2-(ethylsulfonylamino)ethoxy,2-[(2-methylpropyl)sulfonylamino]ethoxy.

(Halogenated C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by an alkylsulfonylamino grouphaving from 1 to 6, preferably from 1 to 4 carbon atoms as definedherein, wherein the alkyl group is halogenated. Examples include2-(trifluoromethylsulfonylamino)ethoxy.

C₆-C₁₂-Arylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radical having from 1to 4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₆-C₁₂-arylsulfonylamino group as definedherein. Examples include 2-(phenylsulfonylamino)ethoxy,2-(naphthylsulfonylamino)ethoxy.

(C₆-C₁₂-Aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by a(C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino group, preferably by a(C₆-C₁₂-aryl-C₁-C₂-alkyl)sulfonylamino group. Examples include2-(benzylsulfonylamino)ethoxy.

C₃-C₁₂-Heterocyclylsulfonylamino-C₁-C₄-alkoxy is an alkoxy radicalhaving from 1 to 4, preferably 1 or 2 carbon atoms as defined herein,wherein one hydrogen atom is replaced by aC₃-C₁₂-heterocyclylsulfonylamino group as defined herein. Examplesinclude 2-(pyridin-3-yl-sulfonylamino)ethoxy.

C₃-C₁₂-Heterocyclyl-C₁-C₄-alkoxy is an alkoxy radical having from 1 to4, preferably 1 or 2 carbon atoms as defined herein, wherein onehydrogen atom is replaced by a C₃-C₁₂-heterocyclyl group as definedherein. Examples include 2-(N-pyrrolidinyl)ethoxy,2-(N-morpholinyl)ethoxy and 2-(N-imidazolyl)ethoxy.

C₁-C₂-Alkylenedioxo is a radical of the formula —O—R—O—, wherein R is astraight-chain or branched alkylene group having from 1 or 2 carbonatoms as defined herein. Examples include methylenedioxo.

C₆-C₁₂-Aryloxy is a radical of the formula R—O—, wherein R is an arylgroup having from 6 to 12, in particular 6 carbon atoms as definedherein. Examples include phenoxy.

C₃-C₁₂-Heterocyclyloxy is a radical of the formula R—O—, wherein R is aC₃-C₁₂-heterocyclyl group having from 3 to 12, in particular from 3 to 7carbon atoms as defined herein. Examples include pyridin-2-yloxy.

C₁-C₆-Alkylthio is a radical of the formula R—S—, wherein R is an alkylradical having from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylthio, ethylthio, propylthio,butylthio, pentylthio, 1-methylbutylthio, 2-methylbutylthio,3-methylbutylthio, 2,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio,1,1-dimethylpropylthio, 1,2-dimethylpropylthio, 1-methylpentylthio,2-methylpentylthio, 3-methylpentylthio, 4-methylpentylthio,1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethylbutylthio,2,2-dimethylbutylthio, 2,3-dimethylbutylthio, 3,3-dimethylbutylthio,1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-trimethylpropylthio,1,2,2-trimethylpropylthio, 1-ethyl-1-methylpropyl and1-ethyl-2-methylpropyl.

Halogenated C₁-C₆-alkylthio is a radical of the formula R—S—, wherein Ris a halogenated alkyl radical having from 1 to 6, preferably from 1 to4 carbon atoms as defined herein. Examples include halogenomethylthio,dihalogenomethylthio, trihalogenomethylthio, (R)-1-halogenoethylthio,(S)-1-halogenoethylthio, 2-halogenoethylthio, 1,1-dihalogenoethylthio,2,2-dihalogenoethylthio, 2,2,2-trihalogenoethylthio,(R)-1-halogenopropylthio, (S)-1-halogenopropylthio,2-halogenopropylthio, 3-halogenopropylthio, 1,1-dihalogenopropylthio,2,2-dihalogenopropylthio, 3,3-dihalogenopropylthio,3,3,3-trihalogenopropylthio, (R)-2-halogeno-1-methylethylthio,(S)-2-halogeno-1-methylethylthio, (R)-2,2-dihalogeno-1-methylethylthio,(S)-2,2-dihalogeno-1-methylethylthio,(R)-1,2-dihalogeno-1-methylethylthio,(S)-1,2-dihalogeno-1-methylethylthio,(R)-2,2,2-trihalogeno-1-methylethylthio,(S)-2,2,2-trihalogeno-1-methylethylthio,2-halogeno-1-(halogenomethyl)ethylthio,1-(dihalogenomethyl)-2,2-dihalogenoethylthio, (R)-1-halogenobutylthio,(S)-1-halogenobutylthio, 2-halogenobutylthio, 3-halogenobutylthio,4-halogenobutylthio, 1,1-dihalogenobutylthio, 2,2-dihalogenobutylthio,3,3-dihalogenobutylthio, 4,4-dihalogenobutylthio,4,4,4-trihalogenobutylthio, etc. Particular examples include thefluorinated C₁-C₄ alkylthio groups as defined, such astrifluoromethylthio.

C₁-C₆-Alkylsulfinyl is a radical of the formula R—S(O)—, wherein R is analkyl radical having from 1 to 6, preferably from 1 to 4 carbon atoms asdefined herein. Examples include methylsulfinyl, ethylsulfinyl,propylsulfinyl, butylsulfinyl, pentylsulfinyl, 1-methylbutylsulfinyl,2-methylbutylsulfinyl, 3-methylbutylsulfinyl,2,2-dimethylpropylsulfinyl, 1-ethylpropylsulfinyl, hexylsulfinyl,1,1-dimethylpropylsulfinyl, 1,2-dimethylpropylsulfinyl,1-methylpentylsulfinyl, 2-methylpentylsulfinyl, 3-methylpentylsulfinyl,4-methylpentylsulfinyl, 1,1-dimethylbutylsulfinyl,1,2-dimethylbutylsulfinyl, 1,3-dimethylbutylsulfinyl,2,2-dimethylbutylsulfinyl, 2,3-dimethylbutylsulfinyl,3,3-dimethylbutylsulfinyl, 1-ethylbutylsulfinyl, 2-ethylbutylsulfinyl,1,1,2-trimethylpropylsulfinyl, 1,2,2-trimethylpropylsulfinyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

C₁-C₆-Alkylsulfonyl is a radical of the formula R—S(O)₂—, wherein R isan alkyl radical having from 1 to 6, preferably from 1 to 4 carbon atomsas defined herein. Examples include methylsulfonyl, ethylsulfonyl,propylsulfonyl, butylsulfonyl, pentylsulfonyl, 1-methylbutylsulfonyl,2-methylbutylsulfonyl, 3-methylbutylsulfonyl,2,2-dimethylpropylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl,1,1-dimethylpropylsulfonyl, 1,2-dimethylpropylsulfonyl,1-methylpentylsulfonyl, 2-methylpentylsulfonyl, 3-methylpentylsulfonyl,4-methylpentylsulfonyl, 1,1-dimethylbutylsulfonyl,1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl,2,2-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl,3,3-dimethylbutylsulfonyl, 1-ethylbutylsulfonyl, 2-ethylbutylsulfonyl,1,1,2-trimethylpropylsulfonyl, 1,2,2-trimethylpropylsulfonyl,1-ethyl-1-methylpropyl and 1-ethyl-2-methylpropyl.

(Halogenated C₁-C₆-alkyl)sulfonyl is a C₁-C₆-alkylsulfonyl as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₆-C₁₂-Arylsulfonyl is a radical of the formula R—S(O)₂—, wherein R isan aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylsulfonyl.

(C₆-C₁₂-Aryl-C₁-C₄-alkyl)sulfonyl is a radical of the formula R—S(O)₂—,wherein R is a C₆-C₁₂-aryl-C₁-C₄-alkyl radical, in particular aC₆-C₁₂-aryl-C₁-C₂-alkyl radical as defined herein. Examples includebenzylsulfonyl.

C₃-C₁₂-Heterocyclylsulfonyl is a radical of the formula R—S(O)₂—,wherein R is C₃-C₁₂-heterocyclyl as defined herein.

Aminosulfonyl is NH₂—S(O)₂—.

C₁-C₆-Alkylaminosulfonyl is a radical of the formula R—NH—S(O)₂— whereinR is an alkyl radical having from 1 to 6, preferably from 1 to 4 carbonatoms as defined herein. Examples include methylaminosulfonyl,ethylaminosulfonyl, n-propylaminosulfonyl, isopropylaminosulfonyl,n-butylaminosulfonyl, 2-butylaminosulfonyl, iso-butylaminosulfonyl,tert-butylaminosulfonyl.

Di-C₁-C₆-alkylaminosulfonyl is a radical of the formula RR′N—S(O)₂—wherein R and R′ are independently of each other an alkyl radical havingfrom 1 to 6, preferably from 1 to 4 carbon atoms as defined herein.Examples include dimethylaminosulfonyl, diethylaminosulfonyl,N-methyl-N-ethylaminosulfonyl.

C₆-C₁₂-Arylaminosulfonyl is a radical of the formula R—NH—S(O)₂— whereinR is an aryl radical having from 6 to 12, preferably 6 carbon atoms asdefined herein.

Amino is NH₂.

C₁-C₆-Alkylamino is a radical of the formula R—NH— wherein R is an alkylradical having from 1 to 6, in particular from 1 to 4 carbon atoms asdefined herein. Examples include methylamino, ethylamino, n-propylamino,iso-propylamino, n-butylamino, 2-butylamino, iso-butylamino,tert-butylamino.

(Halogenated C₁-C₆-alkyl)amino is a C₁-C₆-alkylamino as defined herein,wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogen atoms arereplaced by 1, 2, 3, 4 or a corresponding number of identical ordifferent halogen atoms.

Di-C₁-C₆-alkylamino is a radical of the formula RR′N— wherein R and R′are independently of each other an alkyl radical having from 1 to 6, inparticular from 1 to 4 carbon atoms as defined herein. Examples includedimethylamino, diethylamino, N-methyl-N-ethylamino.

Di-(halogenated C₁-C₆-alkyl)amino is a di-C₁-C₆-alkylamino as definedherein, wherein at least one, e.g. 1, 2, 3, 4 or all of the hydrogenatoms are replaced by 1, 2, 3, 4 or a corresponding number of identicalor different halogen atoms.

C₁-C₆-Alkylcarbonylamino is a radical of the formula R—C(O)—NH—, whereinR is an alkyl radical having from 1 to 6, in particular from 1 to 4carbon atoms as defined herein. Examples includeacetamido(methylcarbonylamino), propionamido, n-butyramido,2-methylpropionamido(isopropylcarbonylamino), 2,2-dimethylpropionamidoand the like.

(Halogenated C₁-C₆-alkyl)carbonylamino is a C₁-C₆-alkylcarbonylamino asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different halogen atoms.

C₆-C₁₂-Arylcarbonylamino is a radical of the formula R—C(O)—NH—, whereinR is an aryl radical having from 6 to 12 carbon atoms as defined herein.Examples include phenylcarbonylamino.

C₂-C₆-Alkenylamino is a radical of the formula R—NH—, wherein R is astraight-chain or branched alkenyl group having from 2 to 6, inparticular 2 to 4 carbon atoms. Examples include vinylamino,allylamino(2-propen-1-ylamino), 1-propen-1-ylamino, 2-propen-2-ylamino,methallylamino(2-methylprop-2-en-1-ylamino) and the like.C₃-C₅-Alkenylamino is, in particular, allylamino,1-methylprop-2-en-1-ylamino, 2-buten-1-ylamino, 3-buten-1-ylamino,methallylamino, 2-penten-1-ylamino, 3-penten-1-ylamino,4-penten-1-ylamino, 1-methylbut-2-en-1-ylamino or2-ethylprop-2-en-1-ylamino.

C₁-C₆-Alkylsulfonylamino is a radical of the formula R—S(O)₂—NH—,wherein R is an alkyl radical having from 1 to 6, in particular from 1to 4 carbon atoms as defined herein. Examples includemethylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino,isopropylsulfonylamino, n-butylsulfonylamino, 2-butylsulfonylamino,iso-butylsulfonylamino, tert-butylsulfonylamino.

(Halogenated C₁-C₆ alkyl)sulfonylamino is a C₁-C₆-alkylsulfonylamino asdefined herein, wherein at least one, e.g. 1, 2, 3, 4 or all of thehydrogen atoms are replaced by 1, 2, 3, 4 or a corresponding number ofidentical or different halogen atoms.

C₆-C₁₂-Arylsulfonylamino is a radical of the formula R—S(O)₂—NH—,wherein R is an aryl radical having from 6 to 12 carbon atoms as definedherein. Examples include phenylsulfonylamino.

Nitro is —NO₂.

C₃-C₁₂-Heterocyclyl is a 3- to 12-membered heterocyclic radicalincluding a saturated heterocyclic radical, which generally has 3, 4, 5,6, or 7 ring forming atoms (ring members), an unsaturated non-aromaticheterocyclic radical, which generally has 5, 6 or 7 ring forming atoms,and a heteroaromatic radical (hetaryl), which generally has 5, 6 or 7ring forming atoms. The heterocyclic radicals may be bound via a carbonatom (C-bound) or a nitrogen atom (N-bound). Preferred heterocyclicradicals comprise 1 nitrogen atom as ring member atom and optionally 1,2 or 3 further heteroatoms as ring members, which are selected,independently of each other from O, S and N. Likewise preferredheterocyclic radicals comprise 1 heteroatom as ring member, which isselected from O, S and N, and optionally 1, 2 or 3 further nitrogenatoms as ring members.

Examples of C₃-C₁₂-heterocyclyl include:

C- or N-bound 3-4-membered, saturated rings, such as

2-oxiranyl, 2-oxetanyl, 3-oxetanyl, 2-aziridinyl, 3-thiethanyl,1-azetidinyl, 2-azetidinyl, 3-azetidinyl;

C-bound, 5-membered, saturated rings, such as

tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl,tetrahydrothien-3-yl, tetrahydropyrrol-2-yl, tetrahydropyrrol-3-yl,tetrahydropyrazol-3-yl, tetrahydro-pyrazol-4-yl,tetrahydroisoxazol-3-yl, tetrahydroisoxazol-4-yl,tetrahydroisoxazol-5-yl, 1,2-oxathiolan-3-yl, 1,2-oxathiolan-4-yl,1,2-oxathiolan-5-yl, tetrahydroisothiazol-3-yl,tetrahydroisothiazol-4-yl, tetrahydroisothiazol-5-yl,1,2-dithiolan-3-yl, 1,2-dithiolan-4-yl, tetrahydroimidazol-2-yl,tetrahydroimidazol-4-yl, tetrahydrooxazol-2-yl, tetrahydrooxazol-4-yl,tetrahydrooxazol-5-yl, tetrahydrothiazol-2-yl, tetrahydrothiazol-4-yl,tetrahydrothiazol-5-yl, 1,3-dioxolan-2-yl, 1,3-dioxolan-4-yl,1,3-oxathiolan-2-yl, 1,3-oxathiolan-4-yl, 1,3-oxathiolan-5-yl,1,3-dithiolan-2-yl, 1,3-dithiolan-4-yl, 1,3,2-dioxathiolan-4-yl;

C-bound, 6-membered, saturated rings, such as

tetrahydropyran-2-yl, tetrahydropyran-3-yl, tetrahydropyran-4-yl,piperidin-2-yl, piperidin-3-yl, piperidin-4-yl,tetrahydrothiopyran-2-yl, tetrahydrothiopyran-3-yl,tetrahydrothiopyran-4-yl, 1,3-dioxan-2-yl, 1,3-dioxan-4-yl,1,3-dioxan-5-yl, 1,4-dioxan-2-yl, 1,3-dithian-2-yl, 1,3-dithian-4-yl,1,3-dithian-5-yl, 1,4-dithian-2-yl, 1,3-oxathian-2-yl,1,3-oxathian-4-yl, 1,3-oxathian-5-yl, 1,3-oxathian-6-yl,1,4-oxathian-2-yl, 1,4-oxathian-3-yl, 1,2-dithian-3-yl,1,2-dithian-4-yl, hexahydropyrimidin-2-yl, hexahydropyrimidin-4-yl,hexahydropyrimidin-5-yl, hexahydropyrazin-2-yl, hexahydropyridazin-3-yl,hexahydropyridazin-4-yl, tetrahydro-1,3-oxazin-2-yl,tetrahydro-1,3-oxazin-4-yl, tetrahydro-1,3-oxazin-5-yl,tetrahydro-1,3-oxazin-6-yl, tetrahydro-1,3-thiazin-2-yl,tetrahydro-1,3-thiazin-4-yl, tetrahydro-1,3-thiazin-5-yl,tetrahydro-1,3-thiazin-6-yl, tetrahydro-1,4-thiazin-2-yl,tetrahydro-1,4-thiazin-3-yl, tetrahydro-1,4-oxazin-2-yl,tetrahydro-1,4-oxazin-3-yl, tetrahydro-1,2-oxazin-3-yl,tetrahydro-1,2-oxazin-4-yl, tetrahydro-1,2-oxazin-5-yl,tetrahydro-1,2-oxazin-6-yl;

N-bound, 5-membered, saturated rings, such as

tetrahydropyrrol-1-yl(pyrrolidin-1-yl), tetrahydropyrazol-1-yl,tetrahydroisoxazol-2-yl, tetrahydroisothiazol-2-yl,tetrahydroimidazol-1-yl, tetrahydrooxazol-3-yl, tetrahydrothiazol-3-yl;

N-bound, 6-membered, saturated rings, such as

piperidin-1-yl, hexahydropyrimidin-1-yl,hexahydropyrazin-1-yl(piperazin-1-yl), hexahydropyridazin-1-yl,tetrahydro-1,3-oxazin-3-yl, tetrahydro-1,3-thiazin-3-yl,tetrahydro-1,4-thiazin-4-yl, tetrahydro-1,4-oxazin-4-yl(morpholin-1-yl),tetrahydro-1,2-oxazin-2-yl;

C-bound, 5-membered, partially unsaturated rings, such as

2,3-dihydrofuran-2-yl, 2,3-dihydrofuran-3-yl, 2,5-dihydrofuran-2-yl,2,5-di-hydrofuran-3-yl, 4,5-dihydrofuran-2-yl, 4,5-dihydrofuran-3-yl,2,3-dihydro-thien-2-yl, 2,3-dihydrothien-3-yl, 2,5-dihydrothien-2-yl,2,5-dihydrothien-3-yl, 4,5-dihydrothien-2-yl, 4,5-dihydrothien-3-yl,2,3-dihydro-1H-pyrrol-2-yl, 2,3-dihydro-1H-pyrrol-3-yl,2,5-dihydro-1H-pyrrol-2-yl, 2,5-dihydro-1H-pyrrol-3-yl,4,5-dihydro-1H-pyrrol-2-yl, 4,5-dihydro-1H-pyrrol-3-yl,3,4-dihydro-2H-pyrrol-2-yl, 3,4-dihydro-2H-pyrrol-3-yl,3,4-dihydro-5H-pyrrol-2-yl, 3,4-dihydro-5H-pyrrol-3-yl,4,5-dihydro-1H-pyrazol-3-yl, 4,5-dihydro-1H-pyrazol-4-yl,4,5-dihydro-1H-pyrazol-5-yl, 2,5-dihydro-1H-pyrazol-3-yl,2,5-dihydro-1H-pyrazol-4-yl, 2,5-dihydro-1H-pyrazol-5-yl,4,5-dihydroisoxazol-3-yl, 4,5-dihydroisoxazol-4-yl,4,5-dihydroisoxazol-5-yl, 2,5-dihydroisoxazol-3-yl,2,5-dihydroisoxazol-4-yl, 2,5-dihydroisoxazol-5-yl,2,3-dihydroisoxazol-3-yl, 2,3-dihydroisoxazol-4-yl,2,3-dihydroisoxazol-5-yl, 4,5-dihydroisothiazol-3-yl,4,5-dihydroisothiazol-4-yl, 4,5-dihydroisothiazol-5-yl,2,5-dihydroisothiazol-3-yl, 2,5-dihydroisothiazol-4-yl,2,5-dihydroisothiazol-5-yl, 2,3-dihydroisothiazol-3-yl,2,3-dihydroisothiazol-4-yl, 2,3-dihydroisothiazol-5-yl,4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl,4,5-dihydro-1H-imidazol-5-yl, 2,5-dihydro-1H-imidazol-2-yl,2,5-dihydro-1H-imidazol-4-yl, 2,5-dihydro-1H-imidazol-5-yl,2,3-dihydro-1H-imidazol-2-yl, 2,3-dihydro-1H-imidazol-4-yl,4,5-dihydro-oxazol-2-yl, 4,5-dihydrooxazol-4-yl, 4,5-dihydrooxazol-5-yl,2,5-dihydrooxazol-2-yl, 2,5-dihydrooxazol-4-yl, 2,5-dihydrooxazol-5-yl,2,3-dihydrooxazol-2-yl, 2,3-dihydrooxazol-4-yl, 2,3-dihydrooxazol-5-yl,4,5-dihydrothiazol-2-yl, 4,5-dihydrothiazol-4-yl,4,5-dihydrothiazol-5-yl, 2,5-dihydrothiazol-2-yl,2,5-dihydrothiazol-4-yl, 2,5-dihydrothiazol-5-yl,2,3-dihydrothiazol-2-yl, 2,3-dihydrothiazol-4-yl,2,3-dihydrothiazol-5-yl, 1,3-dioxol-2-yl, 1,3-dioxol-4-yl,1,3-dithiol-2-yl, 1,3-dithiol-4-yl, 1,3-oxathiol-2-yl,1,3-oxathiol-4-yl, 1,3-oxathiol-5-yl;

C-bound, 6-membered, partially unsaturated rings, such as

2H-3,4-dihydropyran-6-yl, 2H-3,4-dihydropyran-5-yl,2H-3,4-dihydropyran-4-yl, 2H-3,4-dihydropyran-3-yl,2H-3,4-dihydropyran-2-yl, 2H-3,4-dihydrothiopyran-6-yl,2H-3,4-dihydrothiopyran-5-yl, 2H-3,4-dihydrothiopyran-4-yl,2H-3,4-dihydrothiopyran-3-yl, 2H-3,4-dihydrothiopyran-2-yl,1,2,3,4-tetrahydropyridin-6-yl, 1,2,3,4-tetrahydropyridin-5-yl,1,2,3,4-tetrahydropyridin-4-yl, 1,2,3,4-tetra-hydropyridin-3-yl,1,2,3,4-tetrahydropyridin-2-yl, 2H-5,6-dihydropyran-2-yl,2H-5,6-dihydropyran-3-yl, 2H-5,6-dihydropyran-4-yl,2H-5,6-dihydropyran-5-yl, 2H-5,6-dihydropyran-6-yl,2H-5,6-dihydrothiopyran-2-yl, 2H-5,6-dihydrothiopyran-3-yl,2H-5,6-dihydrothiopyran-4-yl, 2H-5,6-dihydrothiopyran-5-yl,2H-5,6-dihydrothiopyran-6-yl, 1,2,5,6-tetrahydropyridin-2-yl,1,2,5,6-tetrahydropyridin-3-yl, 1,2,5,6-tetrahydropyridin-4-yl,1,2,5,6-tetrahydropyridin-5-yl, 1,2,5,6-tetrahydropyridin-6-yl,2,3,4,5-tetrahydropyridin-2-yl, 2,3,4,5-tetrahydropyridin-3-yl,2,3,4,5-tetrahydropyridin-4-yl, 2,3,4,5-tetrahydropyridin-5-yl,2,3,4,5-tetrahydropyridin-6-yl, 4H-pyran-2-yl, 4H-pyran-3-yl-,4H-pyran-4-yl, 4H-thiopyran-2-yl, 4H-thiopyran-3-yl, 4H-thiopyran-4-yl,1,4-dihydropyridin-2-yl, 1,4-dihydropyridin-3-yl,1,4-dihydropyridin-4-yl, 2H-pyran-2-yl, 2H-pyran-3-yl, 2H-pyran-4-yl,2H-pyran-5-yl, 2H-pyran-6-yl, 2H-thiopyran-2-yl, 2H-thiopyran-3-yl,2H-thiopyran-4-yl, 2H-thiopyran-5-yl, 2H-thiopyran-6-yl,1,2-dihydropyridin-2-yl, 1,2-dihydro-pyridin-3-yl,1,2-dihydropyridin-4-yl, 1,2-dihydropyridin-5-yl,1,2-dihydro-pyridin-6-yl, 3,4-dihydropyridin-2-yl,3,4-dihydropyridin-3-yl, 3,4-dihydro-pyridin-4-yl,3,4-dihydropyridin-5-yl, 3,4-dihydropyridin-6-yl,2,5-dihydropyridin-2-yl, 2,5-dihydropyridin-3-yl,2,5-dihydropyridin-4-yl, 2,5-dihydropyridin-5-yl,2,5-dihydropyridin-6-yl, 2,3-dihydropyridin-2-yl,2,3-dihydropyridin-3-yl, 2,3-dihydropyridin-4-yl,2,3-dihydropyridin-5-yl, 2,3-dihydropyridin-6-yl,2H-5,6-dihydro-1,2-oxazin-3-yl, 2H-5,6-dihydro-1,2-oxazin-4-yl,2H-5,6-dihydro-1,2-oxazin-5-yl, 2H-5,6-dihydro-1,2-oxazin-6-yl,2H-5,6-dihydro-1,2-thiazin-3-yl, 2H-5,6-dihydro-1,2-thiazin-4-yl,2H-5,6-dihydro-1,2-thiazin-5-yl, 2H-5,6-dihydro-1,2-thiazin-6-yl,4H-5,6-dihydro-1,2-oxazin-3-yl, 4H-5,6-dihydro-1,2-oxazin-4-yl,4H-5,6-dihydro-1,2-oxazin-5-yl, 4H-5,6-dihydro-1,2-oxazin-6-yl,4H-5,6-dihydro-1,2-thiazin-3-yl, 4H-5,6-dihydro-1,2-thiazin-4-yl,4H-5,6-dihydro-1,2-thiazin-5-yl, 4H-5,6-dihydro-1,2-thiazin-6-yl,2H-3,6-dihydro-1,2-oxazin-3-yl, 2H-3,6-dihydro-1,2-oxazin-4-yl,2H-3,6-dihydro-1,2-oxazin-5-yl, 2H-3,6-dihydro-1,2-oxazin-6-yl,2H-3,6-dihydro-1,2-thiazin-3-yl, 2H-3,6-dihydro-1,2-thiazin-4-yl,2H-3,6-dihydro-1,2-thiazin-5-yl, 2H-3,6-dihydro-1,2-thiazin-6-yl,2H-3,4-dihydro-1,2-oxazin-3-yl, 2H-3,4-dihydro-1,2-oxazin-4-yl,2H-3,4-dihydro-1,2-oxazin-5-yl, 2H-3,4-dihydro-1,2-oxazin-6-yl,2H-3,4-dihydro-1,2-thiazin-3-yl, 2H-3,4-dihydro-1,2-thiazin-4-yl,2H-3,4-dihydro-1,2-thiazin-5-yl, 2H-3,4-dihydro-1,2-thiazin-6-yl,2,3,4,5-tetrahydropyridazin-3-yl, 2,3,4,5-tetrahydropyridazin-4-yl,2,3,4,5-tetrahydropyridazin-5-yl, 2,3,4,5-tetrahydropyridazin-6-yl,3,4,5,6-tetrahydropyridazin-3-yl, 3,4,5,6-tetrahydropyridazin-4-yl,1,2,5,6-tetrahydropyridazin-3-yl, 1,2,5,6-tetrahydropyridazin-4-yl,1,2,5,6-tetra-hydropyridazin-5-yl, 1,2,5,6-tetrahydropyridazin-6-yl,1,2,3,6-tetrahydro-pyridazin-3-yl, 1,2,3,6-tetrahydropyridazin-4-yl,4H-5,6-dihydro-1,3-oxazin-2-yl, 4H-5,6-dihydro-1,3-oxazin-4-yl,4H-5,6-dihydro-1,3-oxazin-5-yl, 4H-5,6-dihydro-1,3-oxazin-6-yl,4H-5,6-dihydro-1,3-thiazin-2-yl, 4H-5,6-dihydro-1,3-thiazin-4-yl,4H-5,6-dihydro-1,3-thiazin-5-yl, 4H-5,6-dihydro-1,3-thiazin-6-yl,3,4,5-6-tetrahydropyrimidin-2-yl, 3,4,5,6-tetrahydropyrimidin-4-yl,3,4,5,6-tetrahydropyrimidin-5-yl, 3,4,5,6-tetrahydropyrimidin-6-yl,1,2,3,4-tetrahydropyrazin-2-yl, 1,2,3,4-tetrahydropyrazin-5-yl,1,2,3,4-tetrahydro-pyrimidin-2-yl, 1,2,3,4-tetrahydropyrimidin-4-yl,1,2,3,4-tetrahydropyrimidin-5-yl, 1,2,3,4-tetrahydropyrimidin-6-yl,2,3-dihydro-1,4-thiazin-2-yl, 2,3-dihydro-1,4-thiazin-3-yl,2,3-dihydro-1,4-thiazin-5-yl, 2,3-dihydro-1,4-thiazin-6-yl,2H-1,3-oxazin-2-yl, 2H-1,3-oxazin-4-yl, 2H-1,3-oxazin-5-yl,2H-1,3-oxazin-6-yl, 2H-1,3-thiazin-2-yl, 2H-1,3-thiazin-4-yl,2H-1,3-thiazin-5-yl, 2H-1,3-thiazin-6-yl, 4H-1,3-oxazin-2-yl,4H-1,3-oxazin-4-yl, 4H-1,3-oxazin-5-yl, 4H-1,3-oxazin-6-yl,4H-1,3-thiazin-2-yl, 4H-1,3-thiazin-4-yl, 4H-1,3-thiazin-5-yl,4H-1,3-thiazin-6-yl, 6H-1,3-oxazin-2-yl, 6H-1,3-oxazin-4-yl,6H-1,3-oxazin-5-yl, 6H-1,3-oxazin-6-yl, 6H-1,3-thiazin-2-yl,6H-1,3-oxazin-4-yl, 6H-1,3-oxazin-5-yl, 6H-1,3-thiazin-6-yl,2H-1,4-oxazin-2-yl, 2H-1,4-oxazin-3-yl, 2H-1,4-oxazin-5-yl,2H-1,4-oxazin-6-yl, 2H-1,4-thiazin-2-yl, 2H-1,4-thiazin-3-yl,2H-1,4-thiazin-5-yl, 2H-1,4-thiazin-6-yl, 4H-1,4-oxazin-2-yl,4H-1,4-oxazin-3-yl, 4H-1,4-thiazin-2-yl, 4H-1,4-thiazin-3-yl,1,4-dihydropyridazin-3-yl, 1,4-dihydropyridazin-4-yl,1,4-dihydropyridazin-5-yl, 1,4-dihydropyridazin-6-yl,1,4-dihydropyrazin-2-yl, 1,2-dihydropyrazin-2-yl,1,2-dihydropyrazin-3-yl, 1,2-dihydropyrazin-5-yl,1,2-dihydropyrazin-6-yl, 1,4-dihydropyrimidin-2-yl,1,4-dihydropyrimidin-4-yl, 1,4-dihydropyrimidin-5-yl,1,4-dihydropyrimidin-6-yl, 3,4-dihydropyrimidin-2-yl,3,4-dihydropyrimidin-4-yl, 3,4-dihydropyrimidin-5-yl or3,4-dihydropyrimidin-6-yl;

N-bound, 5-membered, partially unsaturated rings, such as

2,3-dihydro-1H-pyrrol-1-yl, 2,5-dihydro-1H-pyrrol-1-yl,4,5-dihydro-1H-pyrazol-1-yl, 2,5-dihydro-1H-pyrazol-1-yl,2,3-dihydro-1H-pyrazol-1-yl, 2,5-dihydroisoxazol-2-yl,2,3-dihydroisoxazol-2-yl, 2,5-dihydroisothiazol-2-yl,2,3-dihydroisoxazol-2-yl, 4,5-dihydro-1H-imidazol-1-yl,2,5-dihydro-1H-imidazol-1-yl, 2,3-dihydro-1H-imidazol-1-yl,2,3-dihydrooxazol-3-yl, 2,3-dihydrothiazol-3-yl;

N-bound, 6-membered, partially unsaturated rings, such as

1,2,3,4-tetrahydropyridin-1-yl, 1,2,5,6-tetrahydropyridin-1-yl,1,4-dihydro-pyridin-1-yl, 1,2-dihydropyridin-1-yl,2H-5,6-dihydro-1,2-oxazin-2-yl, 2H-5,6-dihydro-1,2-thiazin-2-yl,2H-3,6-dihydro-1,2-oxazin-2-yl, 2H-3,6-dihydro-1,2-thiazin-2-yl,2H-3,4-dihydro-1,2-oxazin-2-yl, 2H-3,4-dihydro-1,2-thiazin-2-yl,2,3,4,5-tetrahydropyridazin-2-yl, 1,2,5,6-tetrahydropyridazin-1-yl,1,2,5,6-tetrahydropyridazin-2-yl, 1,2,3,6-tetrahydropyridazin-1-yl,3,4,5,6-tetrahydropyrimidin-3-yl, 1,2,3,4-tetrahydropyrazin-1-yl,1,2,3,4-tetrahydropyrimidin-1-yl, 1,2,3,4-tetrahydropyrimidin-3-yl,2,3-dihydro-1,4-thiazin-4-yl, 2H-1,2-oxazin-2-yl, 2H-1,2-thiazin-2-yl,4H-1,4-oxazin-4-yl, 4H-1,4-thiazin-4-yl, 1,4-dihydropyridazin-1-yl,1,4-dihydropyrazin-1-yl, 1,2-dihydropyrazin-1-yl,1,4-dihydropyrimidin-1-yl or 3,4-dihydropyrimidin-3-yl;

C-bound, 5-membered, heteroaromatic rings, such as

2-furyl, 3-furyl, 2-thienyl, 3-thienyl, pyrrol-2-yl, pyrrol-3-yl,pyrazol-3-yl, pyrazol-4-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl,isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, imidazol-2-yl,imidazol-4-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-2-yl,thiazol-4-yl, thiazol-5-yl, 1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl,1,2,4-oxadiazol-3-yl, 1,2,4,-oxadiazol-5-yl, 1,3,4-oxadiazol-2-yl,1,2,3-thiadiazol-4-yl, 1,2,3-thiadiazol-5-yl, 1,2,4-thiadiazol-3-yl,1,2,4-thiadiazol-5-yl, 1,3,4-thiadiazolyl-2-yl, 1,2,3-triazol-4-yl,1,2,4-triazol-3-yl, tetrazol-5-yl;

C-bound, 6-membered, heteroaromatic rings, such as

pyridin-2-yl, pyridin-3-yl, pyridin-4-yl(4-pyridyl), pyridazin-3-yl,pyridazin-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl,pyrazin-2-yl, 1,3,5-triazin-2-yl, 1,2,4-triazin-3-yl,1,2,4-triazin-5-yl, 1,2,4-triazin-6-yl, 1,2,4,5-tetrazin-3-yl;

N-bound, 5-membered, heteroaromatic rings, such as

pyrrol-1-yl, pyrazol-1-yl, imidazol-1-yl, 1,2,3-triazol-1-yl,1,2,4-triazol-1-yl, tetrazol-1-yl.

Heterocyclyl also includes bicyclic heterocycles, which comprise one ofthe described 5- or 6-membered heterocyclic rings and a furtheranellated, saturated or unsaturated or aromatic carbocycle, such as abenzene, cyclohexane, cyclohexene or cyclohexadiene ring, or a furtheranellated 5- or 6-membered heterocyclic ring, this heterocyclic ringbeing saturated or unsaturated or aromatic. These include quinolinyl,isoquinolinyl, indolyl, indolizinyl, isoindolyl, indazolyl, benzofuryl,benzthienyl, benzo[b]thiazolyl, benzoxazolyl, benzthiazolyl andbenzimidazolyl. Examples of 5- or 6-membered heteroaromatic compoundscomprising an anellated cycloalkenyl ring include dihydroindolyl,dihydroindolizinyl, dihydroisoindolyl, dihydrochinolinyl,dihydroisoquinolinyl, chromenyl and chromanyl.

C₃-C₁₂-Heteroarylene is a heteroaryl diradical. Examples includepyrid-2,5-ylene and pyrid-2,4-ylene.

With respect to the compounds' capability of inhibiting glycinetransporter 1, the variables R, R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴, X²,X³, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁷ preferablyhave the following meanings which, when taken alone or in combination,represent particular embodiments of the isoindoline derivatives of theformula (I) or any other formula disclosed herein.

In said formula (I), there may be one or more than one substituent R, R²and/or R³. More particularly, there may be up to 3 substituents R², andup to 7 substituents R³. Preferably there is one substituent R and 1, 2or 3 substituents R². Formula (I) may thus be depicted as follows:

wherein a is 1, 2 or 3, b is 1, 2, 3, 4, 5, 6 or 7 and c is 1. If thereis more than one radical R², these may be the same or differentradicals. If there is more than one radical R³, these may be the same ordifferent radicals.

According to one embodiment, R is cyano.

Preferably, R is R¹-W-A¹-Q-Y-A²-X¹- and R¹, W, A¹, Q, Y, A², X¹, R², R³,R⁴, X², X³, R⁵ are as defined herein.

R¹ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl or n-pentyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g.cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl), halogenatedC₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1-yl or3,3,3-trifluoroprop-1-yl), tri-(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl (e.g.trimethylsilylethyl), hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl(e.g. ethoxyethyl), amino-C₁-C₄-alkyl, C₁-C₆-alkylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylamino-C₁-C₄-alkyl, C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substitutedC₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl, optionally substitutedC₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl (e.g. cyclopropyl orcyclobutyl), C₁-C₆-alkylcarbonyl, C₁-C₆-alkoxycarbonyl, halogenatedC₁-C₆-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl, aminocarbonyl,C₁-C₆-alkylaminocarbonyl, (halogenated C₁-C₄-alkyl)aminocarbonyl,C₆-C₁₂-arylaminocarbonyl, C₂-C₆-alkenyl (e.g. prop-1,2-en-1-yl),C₂-C₆-alkynyl, optionally substituted C₆-C₁₂-aryl (e.g. phenyl,2-methylphenyl), hydroxy, C₁-C₆-alkoxy (e.g. tert-butyloxy), halogenatedC₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy, C₁-C₆-alkoxy-C₁-C₄-alkoxy,amino-C₁-C₄-alkoxy, C₁-C₆-alkylamino-C₁-C₄-alkoxy,di-C₁-C₆-alkylamino-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂-aryl-C₁-C₄-alkoxy,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenatedC₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy,(C₆-C₁₂-aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated C₁-C₆-alkylthio,C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino, di-C₁-C₆-alkylamino(e.g. dimethylamino), di-(halogenated C₁-C₆-alkyl)amino,C₁-C₆-alkylcarbonylamino, (halogenated C₁-C₆-alkyl)carbonylamino,C₆-C₁₂-arylcarbonylamino, C₁-C₆-alkylsulfonylamino, (halogenatedC₁-C₆-alkyl)sulfonylamino, C₆-C₁₂-arylsulfonylamino or optionallysubstituted C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl, 2-thienyl,4-methyl-2-thienyl, 5-methyl-2-thienyl, 5-chloro-2-thienyl,2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl, 1-methyl-1,2-diazol-4-yl,1-ethyl-1,2-diazol-4-yl, 1-difluoromethyl-1,2-diazol-4-yl,2-methyl-1,3-diazol-4-yl, 1-methyl-1,3-diazol-4-yl,2-methyl-1,3-thiazol-5-yl, 2,4-dimethyl-1,3-thiazol-5-yl,3-pyrrolidinyl, 1-methyl-pyrrol-3-yl, 2-pyridyl,1-methyl-1,2-diazol-3-yl, 1-methyl-3-trifluoromethyl-1,2-diazol-4-yl,1,2-dimethyl-1,3-diazol-4-yl, 5-methylisoxazol-3-yl or1-methyl-1,2,4-triazol-3-yl).

Preferably, R¹ is C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl, isopropyl,sec-butyl, n-butyl or n-pentyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g.cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl), halogenatedC₁-C₆-alkyl (e.g. 3-fluoroprop-1-yl, 3-chloroprop-1-yl or3,3,3-trifluoroprop-1-yl), tri-(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl (e.g.trimethylsilylethyl), C₁-C₆-alkoxy-C₁-C₄-alkyl (e.g. ethoxyethyl),amino-C₁-C₄-alkyl, C₁-C₆-alkylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl, C₆-C₁₂-aryl-C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl (e.g. cyclopropyl or cyclobutyl), C₂-C₆-alkenyl (e.g.prop-1,2-en-1-yl), optionally substituted C₆-C₁₂-aryl (e.g. phenyl),hydroxy, C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino,di-C₁-C₆-alkylamino or optionally substituted C₃-C₁₂-heterocyclyl (e.g.3-pyridyl, 2-thienyl, 4-methyl-2-thienyl, 5-methyl-2-thienyl,5-chloro-2-thienyl, 2,5-dimethyl-3-thienyl, 1,2-diazol-4-yl,1-methyl-1,2-diazol-4-yl, 1-ethyl-1,2-diazol-4-yl,1-difluormethyl-1,2-diazol-4-yl, 2-methyl-1,3-diazol-4-yl,1-methyl-1,3-diazol-4-yl, 2-methyl-1,3-thiazol-5-yl,2,4-dimethyl-1,3-thiazol-5-yl or 3-pyrrolidinyl).

In particular, R¹ is C₁-C₆-alkyl (e.g. ethyl or n-propyl),C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl),C₃-C₁₂-cycloalkyl (e.g. cyclobutyl), or optionally substitutedC₃-C₁₂-heterocyclyl (e.g. 3-pyridyl, 1-methyl-1,2-diazol-4-yl,1-methyl-1,3-diazol-4-yl, 3-oxetanyl, 1-methyl-pyrrol-3-yl).

In connection with R¹, substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl or naphthyl, substituted with 1, 2 or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, amino,C₁-C₄-alkylamino, C₁-C₄-dialkylamino, morpholino and piperidinyl. Thesame applies to substituted C₆-C₁₂-aryl in substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl.

In connection with R¹, substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl, such as pyridyl, thienyl, diazolyl,quinolinyl, piperidinyl, piperazinyl or morpholinyl, pyrrolyl,isoxazolyl and triazolyl being further examples of suchC₃-C₁₂-heterocyclyl, substituted with 1, 2 or 3 substituents selectedfrom the group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxycarbonyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylsulfonyl, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino,C₆-C₁₂-arylamino and C₃-C₁₂-heterocyclyl (e.g., morpholino orpiperidinyl). The same applies to substituted C₃-C₁₂-heterocyclyl suchas C₃-C₁₂-heteroaryl in substituted C₃-C₁₂-heterocyclyl-C₁-C₄-alkyl suchas C₃-C₁₂-heteroaryl-C₁-C₄-alkyl.

According to one embodiment, W is —NR⁸— and Y is a bond. According to analternative embodiment, W is a bond and Y is —NR⁹—. According to afurther alternative embodiment, W is a bond and Y is a bond, especiallyif R¹ is a nitrogen-bound radical, e.g. nitrogen-bound heterocyclyl suchas piperazinyl or morpholinyl.

According to one embodiment, Q is —S(O)₂—. According to an alternativeembodiment, Q is —C(O)—.

According to a particular embodiment, -W-A¹-Q-Y- is -W-A¹-S(O)₂-NR⁹-,—NR⁸—S(O)₂—, -A¹-S(O)₂- or —S(O)₂—. According to a further particularembodiment, -W-A¹-Q-Y- is -W-A¹-CO-NR⁹- or —NR⁸—CO—.

A¹ is optionally substituted C₁-C₄-alkylene or a bond. In connectionwith A¹, substituted C₁-C₄-alkylene in particular includesC₁-C₄-alkylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl and cyano. Preferably, A¹ is abond. If A¹ is C₁-C₄-alkylene, W is preferably —NR⁸—.

A² is optionally substituted C₁-C₄-alkylene (e.g. 1,2-ethylene),C₁-C₄-alkylene-CO—, —CO—C₁-C₄-alkylene, C₁-C₄-alkylene-O—C₁-C₄-alkylene,C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene, optionally substitutedC₆-C₁₂-arylene, optionally substituted C₆-C₁₂-heteroarylene or a bond.Additionally, A² may be optionally substituted C₂-C₄-alkenylen oroptionally substituted C₂-C₄-alkynylene. Preferably, A² is optionallysubstituted C₁-C₄-alkylene (e.g. 1,2-ethylene). More preferably, A² isC₁-C₄-alkylene (e.g. 1,2-ethylene). Alternatively, it is preferred thatA² is optionally substituted C₆-C₁₂-arylene, in particularC₆-C₁₂-arylene selected from the group consisting of phen-1,4-ylene andphen-1,3-ylene, or optionally substituted C₆-C₁₂-heteroarylene, inparticular C₆-C₁₂-heteroarylene selected from the group consisting ofpyrid-2,5-ylene and pyrid-2,4-ylene. If A² is a bond, X¹ is preferablyoptionally substituted C₁-C₄-alkylene. Alternatively, if A² is a bond,X¹ is in particular optionally substituted C₂-C₄-alkenylene oroptionally substituted C₂-C₄-alkynylene.

In connection with A², substituted C₁-C₄-alkylene in particular includesC₁-C₄-alkylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.

In connection with A², substituted C₂-C₄-alkenylene or substitutedC₂-C₄-alkynylene in particular includes C₂-C₄-alkenylene orC₂-C₄-alkynylene substituted with 1, 2 or 3 substituents selected fromthe group consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano.

In connection with A², substituted C₆-C₁₂-arylene in particular includesC₆-C₁₂-arylene substituted with 1, 2 or 3 substituents selected from thegroup consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl, C₁-C₄-alkoxycarbonyl,cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy, C₁-C₄-alkylsulfonyl, amino,C₁-C₄-alkylamino, C₁-C₄-dialkylamino, C₆-C₁₂-arylamino andC₃-C₁₂-heterocyclyl (e.g., morpholino or piperidinyl).

In connection with A², substituted C₆-C₁₂-heteroarylene in particularincludes C₆-C₁₂-heteroarylene substituted with 1, 2 or 3 substituentsselected from the group consisting of C₁-C₄-alkyl, C₁-C₄-haloalkyl,C₁-C₄-alkoxycarbonyl, cyano, C₁-C₄-alkoxy, C₁-C₄-haloalkoxy,C₁-C₄-alkylsulfonyl, amino, C₁-C₄-alkylamino, C₁-C₄-dialkylamino,C₆-C₁₂-arylamino and C₃-C₁₂-heterocyclyl (e.g, morpholino orpiperidinyl).

X¹ is —O—, —NR¹¹—, —S— or optionally substituted C₁-C₄-alkylene (e.g.—CH₂—, 1,2-ethylene or 1,3-popylene). In connection with X¹, substitutedC₁-C₄-alkylene in particular includes C₁-C₄-alkylene substituted with 1,2 or 3 substituents selected from the group consisting of halogen,C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyano. Additionally, X¹ may beoptionally substituted C₂-C₄-alkenylene or optionally substitutedC₂-C₄-alkynylene (e.g. propynylene). In connection with X¹, substitutedC₂-C₄-alkenylene or substituted C₂-C₄-alkynylene in particular includesC₂-C₄-alkenylene or C₂-C₄-alkynylene substituted with 1, 2 or 3substituents selected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl and cyano. Preferably, X¹ is —O—, —NR¹¹, —S—. Morepreferably, X¹ is —O—. Alternatively, it is preferred if X¹ isoptionally substituted C₁-C₄-alkylene (e.g. —CH₂—, 1,2-ethylene or1,3-propylene).

According to a particular embodiment, A² is a bond and X¹ is optionallysubstituted C₁-C₄-alkylene, optionally substituted C₂-C₄-alkenylene oroptionally substituted C₂-C₄-alkynylene.

According to a particular embodiment, R¹-W-A¹-Q-Y-A²-X¹- isR¹-S(O)₂-NH-A²-X¹-, R¹-NH-S(O)₂-A²-X¹-, R¹-C(O)-NH-A²-X¹- orR¹-NH-C(O)-A²-X¹-.

According to a particular embodiment, the structural element -Y-A²-X¹-comprises at least 2, 3 or 4 atoms in the main chain. According tofurther particular embodiments the structural element -Y-A²-X¹- has upto 4, 5 or 6 atoms in the main chain, such as 2 to 6, 2 to 5 or 2 to 4atoms in the main chain, especially 2, 3 or 4 atoms in the main chain.

According to a further particular embodiment, -Y-A²-X¹- is—C₁-C₄-alkylene-O— or —NR⁹—C₁-C₄-alkylene-O—, with -Y-A²-X¹- preferablyhaving 2 to 6, 3 to 5 and especially 4 atoms in the main chain.Particular examples of -Y-A²-X¹- include —(CH₂)₃—O— and —NR⁹—(CH₂)₂—O—.In this particular embodiment, R⁹ is as defined herein and preferably R⁹is hydrogen, C₁-C₆-alkyl (e.g. methyl or ethyl) or C₃-C₁₂-cycloalkyl(e.g. cyclopropyl), or R⁹ is C₁-C₄-alkylene that is bound to a carbonatom in A² which is C₁-C₄-alkylene.

According to a further particular embodiment, -Y-A²-X¹- is—NR⁹—C₁-C₄-alkylene- (e.g. —NH—CH₂—, —NH—(CH₂)₂— or —NH—(CH₂)₃—), with-Y-A²-X¹- preferably having 2 to 6, 2 to 5, 2 to 4 and especially 2, 3or 4 atoms in the main chain. In this particular embodiment, R⁹ is asdefined herein and preferably R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methylor ethyl) or C₃-C₁₂-cycloalkyl (e.g. cyclopropyl); or R⁹ isC₁-C₄-alkylene that is bound to a carbon atom in X¹ which isC₁-C₄-alkylene.

According to a further particular embodiment, -Y-A²-X¹- is—NR⁹—C₂-C₄-alkenylene- or —NR⁹—C₂-C₄-alkynylene- (e.g. —NH—CH₂—C≡C—),with -Y-A²-X¹- preferably having 2 to 6, 3 to 5 and especially 4 atomsin the main chain. In this particular embodiment, R⁹ is as definedherein and preferably is R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methyl orethyl) or C₃-C₁₂-cycloalkyl (e.g. cyclopropyl or cyclobutyl).

According to a further particular embodiment, -Y-A²-X¹- is—C₁-C₄-alkylene- (e.g. —(CH₂)₂—), with -Y-A²-X¹- preferably having 2 to6, 2 to 5, 2 to 4 and especially 2 atoms in the main chain.

According to a further particular embodiment, the structural motif-Y-A²-X¹ as disclosed herein is bound to Q being —S(O)₂— or —C(O)—.Particular examples for this embodiment include compounds of theinvention wherein R is R¹-S(O)₂-Y-A²-X¹ or R¹-C(O)-Y-A²-X¹.

The radical R and in particular the radical R¹-W-A¹-Q-Y-A²-X¹- may, inprinciple, be bound to the 4-, 5-, 6, or 7-position of the isoindolineskeleton:

In said formulae, R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴, X², X³, R⁵ are asdefined herein.

Further particular examples include isoindoline derivatives of the aboveformulae wherein the radical R¹-W-A¹-Q-Y-A²-X¹- is replaced by theradical —CN.

Isoindoline derivatives having the radical R¹-W-A¹-Q-Y-A²-X¹- (or theradical —CN) in the 5-, 6-, 7-position are preferred.

Particularly preferred are isoindoline derivatives having the radicalR¹-W-A¹-Q-Y-A²-X¹— (or the radical —CN) in the 6-position.

In addition to the radical R¹-W-A¹-Q-Y-A²-X¹- (or the radical —CN), theisoindoline derivatives of the invention may have one or more than onefurther substituent bound to the benzene ring. In these positions, theskeleton of the isoindoline derivatives may thus be substituted with oneor more than one radical R². If there is more than one radical R², thesemay be the same or different radicals. In particular, in 4-, 5-, 6-and/or 7-position, the isoindoline skeleton may be substituted with oneor more than one radical R². The isoindoline derivatives of theinvention may therefore be represented by one of the following formulae:

or by corresponding formulae wherein the radical R¹-W-A¹-Q-Y-A²-X¹- isreplaced by the radical —CN,

wherein R^(2a), R^(2b), R^(2c), R^(2d) independently have one of themeanings given for R², and R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴, X², X³,R⁵ are as defined herein.

R² is hydrogen, halogen (e.g. fluorine), C₁-C₆-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, —CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl,optionally substituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenatedC₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally substitutedC₃-C₁₂-heterocyclyl, or two radicals R² together with the ring atoms towhich they are bound form a 5- or 6 membered ring.

An optionally substituted 5- or 6-membered ring that is formed by tworadicals R² together with the ring atoms to which they are bound is, forinstance, a benzene ring.

In connection with R², substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl, substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen, C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

In connection with R², substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl, such as morpholinyl, pyrrolidinyl andpiperidinyl, substituted with 1, 2 or 3 substituents selected from thegroup consisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, cyano,C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

Preferably, R² is hydrogen, halogen (e.g. fluorine) or C₁-C₆-alkoxy. Inparticular, R² is hydrogen or halogen (e.g. fluorine).

According to a particular embodiment, the isoindoline derivatives of theinvention have one of the following formulae:

or a corresponding formula wherein the radical R¹-W-A¹-Q-Y-A²-X¹- isreplaced by the radical —CN,wherein R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴, X², X³, R⁵ are as definedherein.

Particularly preferred are isoindoline derivatives of the followingformula:

wherein R¹, W, A¹, Q, Y, A², X¹, R², R³, R⁴, X², X³, R⁵ are as definedherein, with R² preferably being halogen, in particular fluorine.

In 1-, and/or 3-position, the isoindoline derivatives of the inventionmay be substituted with one or more than one radical R³. If there ismore than one radical R³, these may be the same or different radicals.The isoindoline derivatives of the invention may therefore berepresented by the following formula:

wherein R^(3a), R^(3b), R^(3c) independently have one of the meaningsgiven for R³; and R, R², R³, R⁴, X², X³, R⁵ are as defined herein.

R³ is hydrogen, halogen, C₁-C₆-alkyl, C₁-C₆-alkoxy, or two radicals R³(i.e. R^(3a) and R^(3b)) together with the carbon atom to which they areattached form a carbonyl group.

Preferably, R³ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkoxy, or two radicalsR³ together with the carbon atom to which they are attached form acarbonyl group. In particular, R³ is hydrogen or C₁-C₆-alkyl (e.g.methyl), or two radicals R³ together with the carbon atom to which theyare attached form a carbonyl group.

R⁴ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl or isopropyl),C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl), halogenatedC₁-C₄-alkyl (e.g. 2-fluoroethyl or 2,2,2-trifluoroethyl),hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,C₆-C₁₂-aryl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl (e.g. cyclopropyl), CH₂CN,—CHO, C₁-C₄-alkylcarbonyl (e.g. methylcarbonyl, ethylcarbonyl orisopropylcarbonyl), (halogenated C₁-C₄-alkyl)carbonyl (e.g.fluoromethylcarbonyl, difluoromethylcarbonyl, trifluoromethylcarbonyl,1,1,1-trifluoroeth-2-ylcarbonyl or 1,1,1-trifluoroprop-3-ylcarbonyl),C₆-C₁₂-arylcarbonyl (e.g. phenylcarbonyl), C₁-C₄-alkoxycarbonyl (e.g.ethoxycarbonyl or tert-butyloxycarbonyl), C₆-C₁₂-aryloxycarbonyl (e.g.phenoxycarbonyl), C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂,—C(═NH)NHCN, C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO orC₃-C₁₂-heterocyclyl (e.g. 3-oxetanyl).

Preferably, R⁴ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl, n-propyl orisopropyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl),halogenated C₁-C₄-alkyl (e.g. 2-fluoroethyl or 2,2,2-trifluoroethyl),amino-C₁-C₄-alkyl, C₆-C₁₂-aryl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl (e.g.cyclopropyl), CH₂CN, C₁-C₄-alkylcarbonyl (e.g. methylcarbonyl orisopropylcarbonyl), (halogenated C₁-C₄-alkyl)carbonyl (e.g.fluoromethylcarbonyl, difluoromethylcarbonyl ortrifluoromethylcarbonyl), C₆-C₁₂-arylcarbonyl (e.g. phenylcarbonyl),C₁-C₄-alkoxycarbonyl (e.g. ethoxycarbonyl or tert-butyloxycarbonyl),C₆-C₁₂-aryloxycarbonyl (e.g. phenoxycarbonyl), —C(═NH)NH₂, —C(═NH)NHCN,C₁-C₆-alkylsulfonyl, amino, —NO or C₃-C₁₂-heterocyclyl (e.g.3-oxetanyl).

In particular, R⁴ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl orn-propyl), C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl),halogenated C₁-C₄-alkyl (e.g. 1,1,1-trifluoroeth-2-yl),C₃-C₁₂-cycloalkyl (e.g. cyclopropyl), (halogenated C₁-C₄-alkyl)carbonyl(e.g. trifluoromethylcarbonyl), or C₃-C₁₂-heterocyclyl (e.g.3-oxetanyl).

X² is —O—, —NR⁶—, —S—, >CR^(12a)R^(12b) or a bond. Preferably, X² is>CR^(12a)R^(12b).

X³ is —O—, —NR⁷—, —S—, >CR^(13a)R^(13b) or a bond. Preferably, X³ is abond.

Thus, it is preferred if X² is >CR^(12a)R^(12b) and X³ is a bond.

R^(12a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy. Preferably, R^(12a) is hydrogen or C₁-C₆-alkyl.

R^(13a) is hydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy. Preferably, R^(13a) is hydrogen or C₁-C₆-alkyl.

In connection with R^(12a) and R^(13a), substituted C₁-C₆-alkyl inparticular includes C₁-C₆-alkyl substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen, hydroxy, C₁-C₄-alkoxy andamino.

In connection with R^(12a) and R^(13a), substituted C₆-C₁₂-aryl inparticular includes C₆-C₁₂-aryl, such as phenyl, substituted with 1, 2or 3 substituents selected from the group consisting of C₁-C₄-alkyl,C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxy and C₁-C₄-haloalkoxy.

R^(12b) is hydrogen or C₁-C₆-alkyl. According to a particularembodiment, R^(12b) is hydrogen.

R^(13b) is hydrogen or C₁-C₆-alkyl. According to a particularembodiment, R^(13b) is hydrogen.

Alternatively, R^(12a) and R^(12b), or R^(13a) and R^(13b), together arecarbonyl or, preferably, optionally substituted C₁-C₄-alkylene (e.g.1,3-propylene), wherein one —CH₂— of C₁-C₄-alkylene may be replaced byan oxygen atom, or —NR¹⁴— or —NR¹⁵—.

In connection with R^(12a) and R^(12b), or R^(13a) and R^(13b),substituted C₁-C₄-alkylene in particular includes C₁-C₄-alkylenesubstituted with 1, 2 or 3 substituents selected from the groupconsisting of halogen, C₁-C₄-alkyl, C₁-C₄-haloalkyl, cyano, C₁-C₄-alkoxyand C₁-C₄-haloalkoxy.

According to a particular embodiment, R^(12a) is C₁-C₆-alkyl and R^(12b)is hydrogen or C₁-C₆-alkyl, or R^(13a) is C₁-C₆-alkyl and R^(13b) ishydrogen or C₁-C₆-alkyl.

According to a further particular embodiment, R^(12a) is hydrogen andR^(12b) is hydrogen, or

R^(13a) is hydrogen and R^(13b) is hydrogen.

According to a further particular embodiment, R^(12a) and R^(12b)together are optionally substituted 1,3-propylene, or R^(13a) andR^(13b) together are optionally substituted 1,3-propylene.

R⁵ is optionally substituted C₆-C₁₂-aryl (e.g. phenyl, 2-fluorophenyl,2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl; 3-cyanophenyl,3-methylphenyl, 3-trifluoromethylphenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-methoxyphenyl, 3,4-difluorophenyl,3,5-difluorophenyl, 3-fluoro-5-chlorophenyl, 3-chloro-4-fluorophenyl,2,4-dichlorophenyl or 3,4-dichlorophenyl,), optionally substitutedC₃-C₁₂-cycloalkyl (e.g. cyclohexyl) or optionally substitutedC₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₃-C₁₂-cycloalkyl in particularincludes C₃-C₁₂-cycloalkyl, such as cyclopropyl or cyclohexyl,substituted with 1, 2 or 3 substituents selected from the groupconsisting of halogen, optionally substituted C₁-C₆-alkyl, halogenatedC₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy, halogenated C₁-C₆-alkoxy, amino,C₁-C₆-alkylamino, di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₆-C₁₂-aryl in particular includesC₆-C₁₂-aryl, such as phenyl, substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen (e.g. F, Cl, Br),optionally substituted C₁-C₆-alkyl (e.g. methyl), halogenatedC₁-C₆-alkyl (e.g. trifluoromethyl), CN, hydroxy, C₁-C₆-alkoxy (e.g.methoxy), halogenated C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl.

In connection with R⁵, substituted C₃-C₁₂-heterocyclyl in particularincludes C₃-C₁₂-heterocyclyl substituted with 1, 2 or 3 substituentsselected from the group consisting of halogen, optionally substitutedC₁-C₆-alkyl, halogenated C₁-C₆-alkyl, CN, hydroxy, C₁-C₆-alkoxy,halogenated C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino, di-C₁-C₆-alkylaminoand C₃-C₁₂-heterocyclyl.

In connection with R⁵, C₃-C₁₂-heterocyclyl in particular isC₃-C₁₂-heteroaryl.

Preferably, R⁵ is optionally substituted C₆-C₁₂-aryl, in particular asin the isoindoline derivatives of the formula:

wherein R, R², R³, R⁴, X², X³ are as defined herein, and

R^(17a), R^(17b), R^(17c), R^(17d), R^(17e) independently are hydrogen,halogen (e.g. F, Cl or Br), optionally substituted C₁-C₆-alkyl (e.g.methyl), halogenated C₁-C₆-alkyl (e.g. trifluoromethyl), CN, hydroxy,C₁-C₆-alkoxy (e.g. methoxy), amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino or C₃-C₁₂-heterocyclyl.

It is also preferred if R⁵ is optionally substituted C₆-C₁₂-heteroaryl,in particular as in the isoindoline derivatives of the formula:

wherein R, R², R³, R⁴, X², X³ are as defined herein, and

R^(17b), R^(17c), R^(17d), R^(17e) independently are hydrogen, halogen(e.g. F, Cl or Br), optionally substituted C₁-C₆-alkyl (e.g. methyl),halogenated C₁-C₆-alkyl (e.g. trifluoromethyl), CN, hydroxy,C₁-C₆-alkoxy (e.g. methoxy), amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino or C₃-C₁₂-heterocyclyl.

According to a particular embodiment, the invention relates toisoindoline derivatives of the formula:

wherein R, R², R³, R⁴, R⁵ are as defined herein, R⁵ preferably beingoptionally substituted aryl and in particular optionally substitutedphenyl as disclosed herein.

In connection with R⁵ or R^(17a), R^(17b), R^(17c), R^(17d), R^(17e),substituted C₁-C₆-alkyl in particular includes C₁-C₆-alkyl, especiallyC₁-C₄-alkyl, substituted with 1, 2 or 3 substituents selected from thegroup consisting of hydroxy, C₁-C₆-alkoxy, amino, C₁-C₆-alkylamino,di-C₁-C₆-alkylamino and C₃-C₁₂-heterocyclyl (e.g. morpholinyl orpiperidinyl).

According to a particular embodiment, R^(17a), R^(17d), R^(17d), R^(17e)are hydrogen and R^(17c) is different from hydrogen(para-mono-substitution).

According to a further particular embodiment, R^(17a), R^(17c), R^(17d),R^(17e) are hydrogen and R^(17b) is different from hydrogen(meta-mono-substitution).

According to a further particular embodiment, R^(17b), R^(17c), R^(17d),R^(17e) are hydrogen and R^(17a) is different from hydrogen(meta-ortho-substitution).

In connection with R^(17a), R^(17b), R^(17c), R^(17d), R^(17e),C₃-C₁₂-heterocyclyl in particular includes morpholinyl, imidazolyl andpyrazolyl.

R⁶ is hydrogen or C₁-C₆-alkyl. Preferably, R⁶ is hydrogen.

R⁷ is hydrogen or C₁-C₆-alkyl. Preferably, R⁷ is hydrogen.

R⁸ is hydrogen or C₁-C₆-alkyl. Preferably, R⁸ is hydrogen.

R⁹ is hydrogen, C₁-C₆-alkyl (e.g. methyl or ethyl), C₃-C₁₂-cycloalkyl(e.g. cyclopropyl), amino-C₁-C₆-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl or C₃-C₁₂-heterocyclyl (e.g. 3-azetidinyl).Preferably, R⁹ is hydrogen or C₁-C₆-alkyl (e.g. methyl or ethyl).

According to a particular embodiment, R⁹ and R¹ together areC₁-C₄-alkylene (e.g. 1,3-1,2-ethylene or propylene) so as that R⁹ and R¹together with the atom in Q to which R¹ is bound and the nitrogen atomto which R⁹ is bound form an heterocyclic ring having, in particular, 4,5 or 6 ring member atoms (including the nitrogen atom and Q). With W andA¹ both being a bond, such a ring may be represented by the followingpartial structure:

wherein A², X¹, Q are as defined herein (e.g. S(O)₂) and n is 0, 1, 2, 3or 4.

According to a further particular embodiment, R⁹ is C₁-C₄-alkylene (e.g.methylene or 1,3-propylene) that is bound to a carbon atom in A² and A²is C₁-C₄-alkylene so that R⁹ and at least part of A² together with thenitrogen atom to which R⁹ is bound form an N-containing heterocyclicring having, in particular, 4, 5, 6 or 7 ring member atoms (includingthe nitrogen atom). Such a ring may be represented by the followingpartial structure:

wherein R¹, W, A¹, Q and X¹ are as defined herein, p is 1 or 2, r is 0,1 or 2 and q is 0, 1 or 2. In this particular embodiment, X¹ preferablyis —O—. Particular combinations of p, r and q include p=1, r=0, q=1; andp=1, r=0, q=0. Alternatively, p is 0, r is 3 and q is 1, with X¹preferably being —O—.

According to a further particular embodiment, R⁹ is C₁-C₄-alkylene (e.g.methylene or 1,3-propylene) that is bound to a carbon atom in X¹ and X¹is C₁-C₄-alkylene (e.g. 1,2-ethylene) so that R⁹ and at least part of X¹together with the nitrogen atom to which R⁹ is bound form anN-containing heterocyclic ring having, in particular, 4, 5, 6 or 7 ringmember atoms (including the nitrogen atom). With A² being a bond, such aring may be represented by the following partial structure:

wherein R¹, W, A¹ and Q are as defined herein, p is 1 or 2, r is 0, 1 or2 and q is 0, 1 or 2. Particular combinations of p, r and q include p=1,r=0, q=0.

R¹⁰ is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl. Preferably, R¹⁰ ishydrogen.

R¹¹ is hydrogen or C₁-C₆-alkyl. Preferably, R¹¹ is hydrogen.

Alternatively, R⁹, R¹¹ together are C₁-C₄-alkylene (e.g. ethylene).

R¹⁴ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁴ is hydrogen.

R¹⁵ is hydrogen or C₁-C₆-alkyl. Preferably, R¹⁵ is hydrogen.

Particular embodiments of isoindoline derivatives of the inventionresult if

-   R is R¹-W-A¹-Q-Y-A²-X¹-;-   R¹ is C₁-C₆-alkyl (e.g. ethyl or n-propyl),    C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl),    C₃-C₁₂-cycloalkyl (e.g. cyclobutyl), or optionally substituted    C₃-C₁₂-heterocyclyl (e.g. 3-pyridyl, 1-methyl-1,2-diazol-4-yl,    1-methyl-1,3-diazol-4-yl, 3-oxetanyl, 1-methyl-pyrrol-3-yl);-   W is a bond;-   A¹ is a bond;-   Q is —S(O)₂—;-   Y is —NR⁹— or a bond;-   A² is C₁-C₄-alkylene (e.g. 1,2-ethylene) or a bond;-   X¹ is —O— or optionally substituted C₁-C₄-alkylene (e.g. methylene,    1,2-ethylene or 1,3-propylene);-   R² is hydrogen or halogen (e.g. fluorine);-   R³ is hydrogen or C₁-C₆-alkyl, or two radicals R³ together with the    carbon atom to which they are attached form a carbonyl group;-   R⁴ is hydrogen, C₁-C₆-alkyl (e.g. methyl, ethyl or n-propyl),    C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl (e.g. cyclopropylmethyl), halogenated    C₁-C₄-alkyl (e.g. 1,1,1-trifluoroeth-2-yl), C₃-C₁₂-cycloalkyl (e.g.    cyclopropyl), (halogenated C₁-C₄-alkyl)carbonyl (e.g.    trifluoromethylcarbonyl), or C₃-C₁₂-heterocyclyl(e.g. 3-oxetanyl);-   X² is >CR^(12a)R^(12b);-   X³ is a bond;-   R⁵ is optionally substituted phenyl (e.g. phenyl, 2-fluorophenyl,    2-chlorophenyl, 3-fluorophenyl, 3-chlorophenyl,    3-trifluoromethylphenyl, 4-fluorophenyl, 4-chlorophenyl) or    optionally substituted pyridyl (e.g. 2-pyridyl);-   R⁹ is hydrogen, or-   R⁹ is C₁-C₄-alkylene (e.g. methylene) that is bound to a carbon atom    in X¹ and X¹ is C₁-C₄-alkylene (e.g. 1,2-ethylene);-   R^(12a) is hydrogen;-   R^(12b) is hydrogen; or-   R^(12a), R^(12b)    -   together are C₁-C₄-alkylene (e.g. 1,3-propylene).

Further particular compounds of the present invention are the individualisoindoline derivatives of the formula (Id) as listed in the followingtables 1 to 12 and physiologically tolerated salts thereof:

Table 1

Compounds of the formula (Id) wherein R² is hydrogen, R³ is hydrogen,R¹⁷ is hydrogen and the combination of R¹, >CR^(12a)R^(12b), R⁴ for acompound in each case corre sponds to one line of Table A (A-1 toA-448).

Table 2

Compounds of the formula (Id) wherein R² is hydrogen, R³ is hydrogen,R¹⁷ is 3-F and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴for a compound in each case corresponds to one line of Table A (A-1 toA-448).

Table 3

Compounds of the formula (Id) wherein R² is hydrogen, R³ is hydrogen,R¹⁷ is 3-Cl and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴for a compound in each case corresponds to one line of Table A (A-1 toA-448).

Table 4

Compounds of the formula (Id) wherein R² is hydrogen, R³ is hydrogen,R¹⁷ is 3-CF₃ and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴for a compound in each case corresponds to one line of Table A (A-1 toA-448).

Table 5

Compounds of the formula (Id) wherein R² is hydrogen, R³ is hydrogen,R¹⁷ is 4-F and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴for a compound in each case corresponds to one line of Table A (A-1 toA-448).

Table 6

Compounds of the formula (Id) wherein R² is hydrogen, R³ is hydrogen,R¹⁷ is 4-Cl and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴for a compound in each case corresponds to one line of Table A (A-1 toA-448).

Table 7

Compounds of the formula (Id) wherein R² is 7-F, R³ is hydrogen, R¹⁷ ishydrogen and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴ fora compound in each case corresponds to one line of Table A (A-1 toA-448).

Table 8

Compounds of the formula (Id) wherein R² is 7-F, R³ is hydrogen, R¹⁷ is3-F and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴ for acompound in each case corresponds to one line of Table A (A-1 to A-448).

Table 9

Compounds of the formula (Id) wherein R² is 7-F, R³ is hydrogen, R¹⁷ is3-Cl and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴ for acompound in each case corresponds to one line of Table A (A-1 to A-448).

Table 10

Compounds of the formula (Id) wherein R² is 7-F, R³ is hydrogen, R¹⁷ is3-CF₃ and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴ for acompound in each case corresponds to one line of Table A (A-1 to A-448).

Table 11

Compounds of the formula (Id) wherein R² is 7-F, R³ is hydrogen, R¹⁷ is4-F and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴ for acompound in each case corresponds to one line of Table A (A-1 to A-448).

Table 12

Compounds of the formula (Id) wherein R² is 7-F, R³ is hydrogen, R¹⁷ is4-Cl and the combination of R¹, -Y-A²-X¹-, >CR^(12a)R^(12b), R⁴ for acompound in each case corresponds to one line of Table A (A-1 to A-448).

R¹ —Y—A²—X¹— >CR^(12a)R^(12b) R⁴ A-1.

—NH—(CH₂)₃— —CH₂— —H A-2.

—NH—(CH₂)₃— —CH₂— —H A-3.

—NH—(CH₂)₃— —CH₂— —H A-4.

—NH—(CH₂)₃— —CH₂— —H A-5.

—NH—(CH₂)₃— —CH₂— —H A-6.

—NH—(CH₂)₃— —CH₂— —H A-7.

—NH—(CH₂)₃— —CH₂— —H A-8.

—NH—(CH₂)₂—O— —CH₂— —H A-9.

—NH—(CH₂)₂—O— —CH₂— —H A-10.

—NH—(CH₂)₂—O— —CH₂— —H A-11.

—NH—(CH₂)₂—O— —CH₂— —H A-12.

—NH—(CH₂)₂—O— —CH₂— —H A-13.

—NH—(CH₂)₂—O— —CH₂— —H A-14.

—NH—(CH₂)₂—O— —CH₂— —H A-15.

—NH—(CH₂)₂— —CH₂— —H A-16.

—NH—(CH₂)₂— —CH₂— —H A-17.

—NH—(CH₂)₂— —CH₂— —H A-18.

—NH—(CH₂)₂— —CH₂— —H A-19.

—NH—(CH₂)₂— —CH₂— —H A-20.

—NH—(CH₂)₂— —CH₂— —H A-21.

—NH—(CH₂)₂— —CH₂— —H A-22.

—NH—CH₂— —CH₂— —H A-23.

—NH—CH₂— —CH₂— —H A-24.

—NH—CH₂— —CH₂— —H A-25.

—NH—CH₂— —CH₂— —H A-26.

—NH—CH₂— —CH₂— —H A-27.

—NH—CH₂— —CH₂— —H A-28.

—NH—CH₂— —CH₂— —H A-29.

—NH—(CH₂)₃—

—H A-30.

—NH—(CH₂)₃—

—H A-31.

—NH—(CH₂)₃—

—H A-32.

—NH—(CH₂)₃—

—H A-33.

—NH—(CH₂)₃—

—H A-34.

—NH—(CH₂)₃—

—H A-35.

—NH—(CH₂)₃—

—H A-36.

—NH—(CH₂)₂—O—

—H A-37.

—NH—(CH₂)₂—O—

—H A-38.

—NH—(CH₂)₂—O—

—H A-39.

—NH—(CH₂)₂—O—

—H A-40.

—NH—(CH₂)₂—O—

—H A-41.

—NH—(CH₂)₂—O—

—H A-42.

—NH—(CH₂)₂—O—

—H A-43.

—NH—(CH₂)₂—

—H A-44.

—NH—(CH₂)₂—

—H A-45.

—NH—(CH₂)₂—

—H A-46.

—NH—(CH₂)₂—

—H A-47.

—NH—(CH₂)₂—

—H A-48.

—NH—(CH₂)₂—

—H A-49.

—NH—(CH₂)₂—

—H A-50.

—NH—CH₂—

—H A-51.

—NH—CH₂—

—H A-52.

—NH—CH₂—

—H A-53.

—NH—CH₂—

—H A-54.

—NH—CH₂—

—H A-55.

—NH—CH₂—

—H A-56.

—NH—CH₂—

—H A-57.

—NH—(CH₂)₃— —CH₂— —CH₃ A-58.

—NH—(CH₂)₃— —CH₂— —CH₃ A-59.

—NH—(CH₂)₃— —CH₂— —CH₃ A-60.

—NH—(CH₂)₃— —CH₂— —CH₃ A-61.

—NH—(CH₂)₃— —CH₂— —CH₃ A-62.

—NH—(CH₂)₃— —CH₂— —CH₃ A-63.

—NH—(CH₂)₃— —CH₂— —CH₃ A-64.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-65.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-66.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-67.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-68.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-69.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-70.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-71.

—NH—(CH₂)₂— —CH₂— —CH₃ A-72.

—NH—(CH₂)₂— —CH₂— —CH₃ A-73.

—NH—(CH₂)₂— —CH₂— —CH₃ A-74.

—NH—(CH₂)₂— —CH₂— —CH₃ A-75.

—NH—(CH₂)₂— —CH₂— —CH₃ A-76.

—NH—(CH₂)₂— —CH₂— —CH₃ A-77.

—NH—(CH₂)₂— —CH₂— —CH₃ A-78.

—NH—CH₂— —CH₂— —CH₃ A-79.

—NH—CH₂— —CH₂— —CH₃ A-80.

—NH—CH₂— —CH₂— —CH₃ A-81.

—NH—CH₂— —CH₂— —CH₃ A-82.

—NH—CH₂— —CH₂— —CH₃ A-83.

—NH—CH₂— —CH₂— —CH₃ A-84.

—NH—CH₂— —CH₂— —CH₃ A-85.

—NH—(CH₂)₃—

—CH₃ A-86.

—NH—(CH₂)₃—

—CH₃ A-87.

—NH—(CH₂)₃—

—CH₃ A-88.

—NH—(CH₂)₃—

—CH₃ A-89.

—NH—(CH₂)₃—

—CH₃ A-90.

—NH—(CH₂)₃—

—CH₃ A-91.

—NH—(CH₂)₃—

—CH₃ A-92.

—NH—(CH₂)₂—O—

—CH₃ A-93.

—NH—(CH₂)₂—O—

—CH₃ A-94.

—NH—(CH₂)₂—O—

—CH₃ A-95.

—NH—(CH₂)₂—O—

—CH₃ A-96.

—NH—(CH₂)₂—O—

—CH₃ A-97.

—NH—(CH₂)₂—O—

—CH₃ A-98.

—NH—(CH₂)₂—O—

—CH₃ A-99.

—NH—(CH₂)₂—

—CH₃ A-100.

—NH—(CH₂)₂—

—CH₃ A-101.

—NH—(CH₂)₂—

—CH₃ A-102.

—NH—(CH₂)₂—

—CH₃ A-103.

—NH—(CH₂)₂—

—CH₃ A-104.

—NH—(CH₂)₂—

—CH₃ A-105.

—NH—(CH₂)₂—

—CH₃ A-106.

—NH—CH₂—

—CH₃ A-107.

—NH—CH₂—

—CH₃ A-108.

—NH—CH₂—

—CH₃ A-109.

—NH—CH₂—

—CH₃ A-110.

—NH—CH₂—

—CH₃ A-111.

—NH—CH₂—

—CH₃ A-112.

—NH—CH₂—

—CH₃ A-113.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-114.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-115.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-116.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-117.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-118.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-119.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-120.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-121.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-122.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-123.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-124.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-125.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-126.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-127.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-128.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-129.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-130.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-131.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-132.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-133.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-134.

—NH—CH₂— —CH₂— —CH₂CH₃ A-135.

—NH—CH₂— —CH₂— —CH₂CH₃ A-136.

—NH—CH₂— —CH₂— —CH₂CH₃ A-137.

—NH—CH₂— —CH₂— —CH₂CH₃ A-138.

—NH—CH₂— —CH₂— —CH₂CH₃ A-139.

—NH—CH₂— —CH₂— —CH₂CH₃ A-140.

—NH—CH₂— —CH₂— —CH₂CH₃ A-141.

—NH—(CH₂)₃—

—CH₂CH₃ A-142.

—NH—(CH₂)₃—

—CH₂CH₃ A-143.

—NH—(CH₂)₃—

—CH₂CH₃ A-144.

—NH—(CH₂)₃—

—CH₂CH₃ A-145.

—NH—(CH₂)₃—

—CH₂CH₃ A-146.

—NH—(CH₂)₃—

—CH₂CH₃ A-147.

—NH—(CH₂)₃—

—CH₂CH₃ A-148.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-149.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-150.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-151.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-152.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-153.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-154.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-155.

—NH—(CH₂)₂—

—CH₂CH₃ A-156.

—NH—(CH₂)₂—

—CH₂CH₃ A-157.

—NH—(CH₂)₂—

—CH₂CH₃ A-158.

—NH—(CH₂)₂—

—CH₂CH₃ A-159.

—NH—(CH₂)₂—

—CH₂CH₃ A-160.

—NH—(CH₂)₂—

—CH₂CH₃ A-161.

—NH—(CH₂)₂—

—CH₂CH₃ A-162.

—NH—CH₂—

—CH₂CH₃ A-163.

—NH—CH₂—

—CH₂CH₃ A-164.

—NH—CH₂—

—CH₂CH₃ A-165.

—NH—CH₂—

—CH₂CH₃ A-166.

—NH—CH₂—

—CH₂CH₃ A-167.

—NH—CH₂—

—CH₂CH₃ A-168.

—NH—CH₂—

—CH₂CH₃ A-169.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-170.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-171.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-172.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-173.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-174.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-175.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-176.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-177.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-178.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-179.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-180.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-181.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-182.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-183.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-184.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-185.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-186.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-187.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃—CH₂CH₃ A-188.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-189.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-190.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-191.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-192.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-193.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-194.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-195.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-196.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-197.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-198.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-199.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-200.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-201.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-202.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-203.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-204.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-205.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-206.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-207.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-208.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-209.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-210.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-211.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-212.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-213.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-214.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-215.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-216.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-217.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-218.

—NH—CH₂—

—CH₂CH₂CH₃ A-219.

—NH—CH₂—

—CH₂CH₂CH₃ A-220.

—NH—CH₂—

—CH₂CH₂CH₃ A-221.

—NH—CH₂—

—CH₂CH₂CH₃ A-222.

—NH—CH₂—

—CH₂CH₂CH₃ A-223.

—NH—CH₂—

—CH₂CH₂CH₃ A-224.

—NH—CH₂—

—CH₂CH₂CH₃ A-225.

—NH—(CH₂)₃— —CH₂— —H A-226.

—NH—(CH₂)₃— —CH₂— —H A-227.

—NH—(CH₂)₃— —CH₂— —H A-228.

—NH—(CH₂)₃— —CH₂— —H A-229.

—NH—(CH₂)₃— —CH₂— —H A-230.

—NH—(CH₂)₃— —CH₂— —H A-231.

—NH—(CH₂)₃— —CH₂— —H A-232.

—NH—(CH₂)₂—O— —CH₂— —H A-233.

—NH—(CH₂)₂—O— —CH₂— —H A-234.

—NH—(CH₂)₂—O— —CH₂— —H A-235.

—NH—(CH₂)₂—O— —CH₂— —H A-236.

—NH—(CH₂)₂—O— —CH₂— —H A-237.

—NH—(CH₂)₂—O— —CH₂— —H A-238.

—NH—(CH₂)₂—O— —CH₂— —H A-239.

—NH—(CH₂)₂— —CH₂— —H A-240.

—NH—(CH₂)₂— —CH₂— —H A-241.

—NH—(CH₂)₂— —CH₂— —H A-242.

—NH—(CH₂)₂— —CH₂— —H A-243.

—NH—(CH₂)₂— —CH₂— —H A-244.

—NH—(CH₂)₂— —CH₂— —H A-245.

—NH—(CH₂)₂— —CH₂— —H A-246.

—NH—CH₂— —CH₂— —H A-247.

—NH—CH₂— —CH₂— —H A-248.

—NH—CH₂— —CH₂— —H A-249.

—NH—CH₂— —CH₂— —H A-250.

—NH—CH₂— —CH₂— —H A-251.

—NH—CH₂— —CH₂— —H A-252.

—NH—CH₂— —CH₂— —H A-253.

—NH—(CH₂)₃—

—H A-254.

—NH—(CH₂)₃—

—H A-255.

—NH—(CH₂)₃—

—H A-256.

—NH—(CH₂)₃—

—H A-257.

—NH—(CH₂)₃—

—H A-258.

—NH—(CH₂)₃—

—H A-259.

—NH—(CH₂)₃—

—H A-260.

—NH—(CH₂)₂—O—

—H A-261.

—NH—(CH₂)₂—O—

—H A-262.

—NH—(CH₂)₂—O—

—H A-263.

—NH—(CH₂)₂—O—

—H A-264.

—NH—(CH₂)₂—O—

—H A-265.

—NH—(CH₂)₂—O—

—H A-266.

—NH—(CH₂)₂—O—

—H A-267.

—NH—(CH₂)₂—

—H A-268.

—NH—(CH₂)₂—

—H A-269.

—NH—(CH₂)₂—

—H A-270.

—NH—(CH₂)₂—

—H A-271.

—NH—(CH₂)₂—

—H A-272.

—NH—(CH₂)₂—

—H A-273.

—NH—(CH₂)₂—

—H A-274.

—NH—CH₂—

—H A-275.

—NH—CH₂—

—H A-276.

—NH—CH₂—

—H A-277.

—NH—CH₂—

—H A-278.

—NH—CH₂—

—H A-279.

—NH—CH₂—

—H A-280.

—NH—CH₂—

—H A-281.

—NH—(CH₂)₃— —CH₂— —CH₃ A-282.

—NH—(CH₂)₃— —CH₂— —CH₃ A-283.

—NH—(CH₂)₃— —CH₂— —CH₃ A-284.

—NH—(CH₂)₃— —CH₂— —CH₃ A-285.

—NH—(CH₂)₃— —CH₂— —CH₃ A-286.

—NH—(CH₂)₃— —CH₂— —CH₃ A-287.

—NH—(CH₂)₃— —CH₂— —CH₃ A-288.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-289.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-290.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-291.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-292.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-293.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-294.

—NH—(CH₂)₂—O— —CH₂— —CH₃ A-295.

—NH—(CH₂)₂— —CH₂— —CH₃ A-296.

—NH—(CH₂)₂— —CH₂— —CH₃ A-297.

—NH—(CH₂)₂— —CH₂— —CH₃ A-298.

—NH—(CH₂)₂— —CH₂— —CH₃ A-299.

—NH—(CH₂)₂— —CH₂— —CH₃ A-300.

—NH—(CH₂)₂— —CH₂— —CH₃ A-301.

—NH—(CH₂)₂— —CH₂— —CH₃ A-302.

—NH—CH₂— —CH₂— —CH₃ A-303.

—NH—CH₂— —CH₂— —CH₃ A-304.

—NH—CH₂— —CH₂— —CH₃ A-305.

—NH—CH₂— —CH₂— —CH₃ A-306

—NH—CH₂— —CH₂— —CH₃ A-307.

—NH—CH₂— —CH₂— —CH₃ A-308

—NH—CH₂— —CH₂— —CH₃ A-309.

—NH—(CH₂)₃—

—CH₃ A-310.

—NH—(CH₂)₃—

—CH₃ A-311.

—NH—(CH₂)₃—

—CH₃ A-312.

—NH—(CH₂)₃—

—CH₃ A-313.

—NH—(CH₂)₃—

—CH₃ A-314.

—NH—(CH₂)₃—

—CH₃ A-315.

—NH—(CH₂)₃—

—CH₃ A-316.

—NH—(CH₂)₂—O—

—CH₃ A-317.

—NH—(CH₂)₂—O—

—CH₃ A-318.

—NH—(CH₂)₂—O—

—CH₃ A-319.

—NH—(CH₂)₂—O—

—CH₃ A-320.

—NH—(CH₂)₂—O—

—CH₃ A-321.

—NH—(CH₂)₂—O—

—CH₃ A-322.

—NH—(CH₂)₂—O—

—CH₃ A-323.

—NH—(CH₂)₂—

—CH₃ A-324.

—NH—(CH₂)₂—

—CH₃ A-325.

—NH—(CH₂)₂—

—CH₃ A-326.

—NH—(CH₂)₂—

—CH₃ A-327.

—NH—(CH₂)₂—

—CH₃ A-328.

—NH—(CH₂)₂—

—CH₃ A-329.

—NH—(CH₂)₂—

—CH₃ A-330.

—NH—CH₂—

—CH₃ A-331.

—NH—CH₂—

—CH₃ A-332.

—NH—CH₂—

—CH₃ A-333.

—NH—CH₂—

—CH₃ A-334.

—NH—CH₂—

—CH₃ A-335.

—NH—CH₂—

—CH₃ A-336.

—NH—CH₂—

—CH₃ A-337.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-338.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-339.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-340.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-341.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-342.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-343.

—NH—(CH₂)₃— —CH₂— —CH₂CH₃ A-344.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-345.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-346.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-347.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-348.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-349.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-350.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₃ A-351.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-352.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-353.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-354.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-355.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-356.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-357.

—NH—(CH₂)₂— —CH₂— —CH₂CH₃ A-358.

—NH—CH₂— —CH₂— —CH₂CH₃ A-359.

—NH—CH₂— —CH₂— —CH₂CH₃ A-360.

—NH—CH₂— —CH₂— —CH₂CH₃ A-361.

—NH—CH₂— —CH₂— —CH₂CH₃ A-362.

—NH—CH₂— —CH₂— —CH₂CH₃ A-363.

—NH—CH₂— —CH₂— —CH₂CH₃ A-364.

—NH—CH₂— —CH₂— —CH₂CH₃ A-365.

—NH—(CH₂)₃—

—CH₂CH₃ A-366.

—NH—(CH₂)₃—

—CH₂CH₃ A-367.

—NH—(CH₂)₃—

—CH₂CH₃ A-368.

—NH—(CH₂)₃—

—CH₂CH₃ A-369.

—NH—(CH₂)₃—

—CH₂CH₃ A-370.

—NH—(CH₂)₃—

—CH₂CH₃ A-371.

—NH—(CH₂)₃—

—CH₂CH₃ A-372.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-373.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-374.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-375.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-376.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-377.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-378.

—NH—(CH₂)₂—O—

—CH₂CH₃ A-379.

—NH—(CH₂)₂—

—CH₂CH₃ A-380.

—NH—(CH₂)₂—

—CH₂CH₃ A-381.

—NH—(CH₂)₂—

—CH₂CH₃ A-382.

—NH—(CH₂)₂—

—CH₂CH₃ A-383.

—NH—(CH₂)₂—

—CH₂CH₃ A-384.

—NH—(CH₂)₂—

—CH₂CH₃ A-385.

—NH—(CH₂)₂—

—CH₂CH₃ A-386.

—NH—CH₂—

—CH₂CH₃ A-387.

—NH—CH₂—

—CH₂CH₃ A-388.

—NH—CH₂—

—CH₂CH₃ A-389.

—NH—CH₂—

—CH₂CH₃ A-390.

—NH—CH₂—

—CH₂CH₃ A-391.

—NH—CH₂—

—CH₂CH₃ A-392.

—NH—CH₂—

—CH₂CH₃ A-393.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-394.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-395.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-396.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-397.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-398.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-399.

—NH—(CH₂)₃— —CH₂— —CH₂CH₂CH₃ A-400.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-401.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-402.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-403.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-404.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-405.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-406.

—NH—(CH₂)₂—O— —CH₂— —CH₂CH₂CH₃ A-407.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-408.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-409.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-410.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-411.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃—CH₂CH₃ A-412.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-413.

—NH—(CH₂)₂— —CH₂— —CH₂CH₂CH₃ A-414.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-415.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-416.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-417.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-418.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-419.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-420.

—NH—CH₂— —CH₂— —CH₂CH₂CH₃ A-421.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-422.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-423.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-424.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-425.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-426.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-427.

—NH—(CH₂)₃—

—CH₂CH₂CH₃ A-428.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-429.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-430.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-431.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-432.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-433.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-434.

—NH—(CH₂)₂—O—

—CH₂CH₂CH₃ A-435.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-436.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-437.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-438.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-439.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-440.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-441.

—NH—(CH₂)₂—

—CH₂CH₂CH₃ A-442.

—NH—CH₂—

—CH₂CH₂CH₃ A-443.

—NH—CH₂—

—CH₂CH₂CH₃ A-444.

—NH—CH₂—

—CH₂CH₂CH₃ A-445.

—NH—CH₂—

—CH₂CH₂CH₃ A-446.

—NH—CH₂—

—CH₂CH₂CH₃ A-447.

—NH—CH₂—

—CH₂CH₂CH₃ A-448.

—NH—CH₂—

—CH₂CH₂CH₃

Further particular compounds of the present invention are the individualisoindoline derivatives of the formula (Id) as listed in tables 1 to 12and physiologically tolerated salts thereof wherein the radicalR¹-S(O)₂-Y-A²-X¹- is replaced by the radical —CN.

Further particular compounds of the present invention are theisoindoline derivatives disclosed in preparation examples andphysiologically tolerated salts thereof. These include for eachpreparation example the exemplified compound as well as thecorresponding free base and any other physiologically tolerated salts ofthe free base (if the exemplified compound is a salt), or anyphysiologically tolerated salt of the free base (if the exemplifiedcompound is a free base). These further include enantiomers,diastereomers, tautomers and any other isomeric forms of said compounds,be they explicitly or implicitly disclosed.

The compounds of the formula (I) can be prepared by analogy to methodswhich are well known in the art. Suitable methods for the preparation ofcompounds of formula (I) are outlined in the following schemes.

The acid addition salts of the isoindoline derivatives of formula (I)are prepared in a customary manner by mixing the free base with acorresponding acid, optionally in solution in an organic solvent, forexample a lower alcohol, such as methanol, ethanol or propanol, anether, such as methyl tert-butyl ether or diisopropyl ether, a ketone,such as acetone or methyl ethyl ketone, or an ester, such as ethylacetate.

The isoindolines derivatives of formula (II):

wherein L is an amino-protecting group, Y is NR⁹, and A², X¹, R², R³,R⁴, X², X³, R⁵ are defined as herein are useful as intermediates in thepreparation of GlyT1 inhibitors, in particular those of formula (I).

Suitable amino-protecting groups are well known in the art such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991.

According to a particular embodiment, L is optionally substitutedalkylcarbonyl (e.g., tertbutylcarbonyl), optionally substitutedarylcarbonyl, optionally substituted arylalkycarbonyl (e.g.,benzylcarbonyl), optionally substituted alkoxycarbonyl (e.g.,methoxycarbonyl or tert-butyloxycarbonyl), optionally substitutedaryloxycarbonyl (e.g. phenoxycarbonyl) or optionally substitutedarylalkoxycarbonyl.

The compounds of the formula (I) are capable of inhibiting the activityof glycine transporter, in particular glycine transporter 1 (GlyT1).

The utility of the compounds in accordance with the present invention asinhibiting the glycine transporter activity, in particular GlyT1activity, may be demonstrated by methodology known in the art. Forinstance, human GlyT1c expressing recombinant hGlyT1c_5_CHO cells can beused for measuring glycine uptake and its inhibition (IC₅₀) by acompound of formula (I).

Amongst the compounds of the formula (I) those are preferred whichachieve effective inhibition at low concentrations. In particular,compounds of the formula (I) are preferred which inhibit glycinetransporter 1 (GlyT1) at a level of IC₅₀<1 μMol, more preferably at alevel of IC₅₀<0.5 μMol, particularly preferably at a level of IC₅₀<0.2μMol and most preferably at a level of IC₅₀<0.1 μMol.

The compounds of formula (I) display good to moderate metabolicstability.

The metabolic stability of a compound can be measured for example byincubating a solution of this compound with liver microsomes fromparticular species (for example rat, dog or human) and determining thehalf-life of the compound under these conditions (RS Obach, Curr OpinDrug Discov Devel. 2001, 4, 36-44). It is possible in this connection toconclude from an observed longer half-life that the metabolic stabilityof the compound is improved. The stability in the presence of humanliver microsomes is of particular interest because it makes it possibleto predict the metabolic degradation of the compound in the human liver.Compounds with increased metabolic stability (measured in the livermicrosome test) are therefore probably also degraded more slowly in theliver. The slower metabolic degradation in the liver may lead to higherand/or longer-lasting concentrations (active levels) of the compound inthe body, so that the elimination half-life of the compounds of theinvention is increased. Increased and/or longer-lasting active levelsmay lead to a better activity of the compound in therapeutic treatment.In addition, an improved metabolic stability may lead to an increasedbioavailability after oral administration, because the compound issubject, after absorption in the intestine, to less metabolicdegradation in the liver (so-called first pass effect). An increasedoral bioavailability may, owing to an increased concentration (activelevel) of the compound, lead to a better activity of the compound afteroral administration.

Amongst the compounds of the formula (I) those are particularlypreferred which display good to moderate metabolic stability towardshuman liver microsomes. In particular, compounds of the formula (I) arepreferred which display a microsomal clearance at a level of mCl<1000μl/min/mg, more preferably at a level of mCl<500 μl/min/mg, particularlypreferably at a level of mCl<100 μl/min/mg and most preferably at alevel of mCl<50 μl/min/mg.

The compounds of the formula (I) according to the present invention arethus useful as pharmaceuticals.

The present invention therefore also relates to pharmaceuticalcompositions which comprise an inert carrier and a compound of theformula (I).

The present invention also relates to the use of the compounds of theformula (I) in the manufacture of a medicament for inhibiting theglycine transporter GlyT1, and to corresponding methods of inhibitingthe glycine transporter GlyT1.

The NMDA receptor is central to a wide range of CNS processes, and itsrole in a variety of diseases in humans or other species has beendescribed. GlyT1 inhibitors slow the removal of glycine from thesynapse, causing the level of synaptic glycine to rise. This in turnincreases the occupancy of the glycine binding site on the NMDAreceptor, which increases activation of the NMDA receptor followingglutamate release from the presynaptic terminal. Glycine transportinhibitors and in particular inhibitors of the glycine transporter GlyT1are thus known to be useful in treating a variety of neurologic andpsychiatric disorders. Further, glycine A receptors play a role in avariety of diseases in humans or other species. Increasing extracellularglycine concentrations by inhibiting glycine transport may enhance theactivity of glycine A receptors. Glycine transport inhibitors and inparticular inhibitors of the glycine transporter GlyT1 are thus usefulin treating a variety of neurologic and psychiatric disorders.

The present invention thus further relates to the use of the compoundsof the formula (I) for the manufacture of a medicament for treating aneurologic or psychiatric disorder, and to corresponding methods oftreating said disorders.

According to a particular embodiment, the disorder is associated withglycinergic or glutamatergic neurotransmission dysfunction.

According to a further particular embodiment, the disorder is one ormore of the following conditions or diseases: schizophrenia or apsychotic disorder including schizophrenia (paranoid, disorganized,catatonic or undifferentiated), schizophreniform disorder,schizoaffective disorder, delusional disorder, brief psychotic disorder,shared psychotic disorder, psychotic disorder due to a general medicalcondition and substance-induced psychotic disorder, including both thepositive and the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeldt-Jacob disease, perinatal hypoxia, other generalmedical conditions or substance abuse); delirium, amnestic disorders orcognitive impairment including age related cognitive decline; anxietydisorders including acute stress disorder, agoraphobia, generalizedanxiety disorder, obsessive-compulsive disorder, panic attack, panicdisorder, post-traumatic stress disorder, separation anxiety disorder,social phobia, specific phobia, substance-induced anxiety disorder andanxiety due to a general medical condition; substance-related disordersand addictive behaviors (including substance-induced delirium,persisting dementia, persisting amnestic disorder, psychotic disorder oranxiety disorder; tolerance, dependence or withdrawal from substancesincluding alcohol, amphetamines, cannabis, cocaine, hallucinogens,inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics oranxiolytics); obesity, bulimia nervosa and compulsive eating disorders;bipolar disorders, mood disorders including depressive disorders;depression including unipolar depression, seasonal depression andpost-partum depression, premenstrual syndrome (PMS) and premenstrualdysphoric disorder (PDD), mood disorders due to a general medicalcondition, and substance-induced mood disorders; learning disorders,pervasive developmental disorder including autistic disorder, attentiondeficit disorders including attention-deficit hyperactivity disorder(ADHD) and conduct disorder; movement disorders, including akinesias andakinetic-rigid syndromes (including Parkinson's disease, drug-inducedparkinsonism, postencephalitic parkinsonism, progressive supranuclearpalsy, multiple system atrophy, corticobasal degeneration,parkinsonism-ALS dementia complex and basal ganglia calcification),medication-induced parkinsonism (such as neuroleptic-inducedparkinsonism, neuroleptic malignant syndrome, neuroleptic-induced acutedystonia, neuroleptic-induced acute akathisia, neuroleptic-inducedtardive dyskinesia and medication-induced postural tremor), Gilles de laTourette's syndrome, epilepsy, muscular spasms and disorders associatedwith muscular spasticity or weakness including tremors; dyskinesias[including tremor (such as rest tremor, postural tremor and intentiontremor), chorea (such as Sydenham's chorea, Huntington's disease, benignhereditary chorea, neuroacanthocytosis, symptomatic chorea, drug-inducedchorea and hemiballism), myoclonus (including generalised myoclonus andfocal myoclonus), tics (including simple tics, complex tics andsymptomatic tics), and dystonia (including generalised dystonia such asiodiopathic dystonia, drug-induced dystonia, symptomatic dystonia andparoxymal dystonia, and focal dystonia such as blepharospasm,oromandibular dystonia, spasmodic dysphonia, spasmodic torticollis,axial dystonia, dystonic writer's cramp and hemiplegic dystonia)];urinary incontinence; neuronal damage including ocular damage,retinopathy or macular degeneration of the eye, tinnitus, hearingimpairment and loss, and brain edema; emesis; and sleep disordersincluding insomnia and narcolepsy.

According to a further particular embodiment, the disorder is pain, inparticular chronic pain and especially neuropathic pain.

Pain can be classified as acute and chronic pain. Acute pain and chronicpain differ in their etiology, pathophysiology, diagnosis and treatment.

Acute pain, which occurs following tissue injury, is self-limiting,serves as an alert to ongoing tissue damage and following tissue repairit will usually subside. There are minimal psychological symptomsassociated with acute pain apart from mild anxiety. Acute pain isnociceptive in nature and occurs following chemical, mechanical andthermal stimulation of A-delta and C-polymodal pain receptors.

Chronic pain, on the other hand, serves no protective biologicalfunction. Rather than being the symptom of tissue damage it is a diseasein its own right. Chronic pain is unrelenting and not self-limiting andcan persist for years, perhaps decades after the initial injury. Chronicpain can be refractory to multiple treatment regimes. Psychologicalsymptoms associated with chronic pain include chronic anxiety, fear,depression, sleeplessness and impairment of social interaction. Chronicnon-malignant pain is predominantly neuropathic in nature and involvesdamage to either the peripheral or central nervous systems.

Acute pain and chronic pain are caused by different neuro-physiologicalprocesses and therefore tend to respond to different types oftreatments. Acute pain can be somatic or visceral in nature. Somaticpain tends to be a well localised, constant pain and is described assharp, aching, throbbing or gnawing. Visceral pain, on the other hand,tends to be vague in distribution, paroxysmal in nature and is usuallydescribed as deep, aching, squeezing or colicky in nature. Examples ofacute pain include post-operative pain, pain associated with trauma andthe pain of arthritis. Acute pain usually responds to treatment withopioids or non-steroidal anti-inflammatory drugs.

Chronic pain, in contrast to acute pain, is described as burning,electric, tingling and shooting in nature. It can be continuous orparoxysmal in presentation. The hallmarks of chronic pain are chronicallodynia and hyperalgesia. Allodynia is pain resulting from a stimulusthat normally does not ellicit a painful response, such as a lighttouch. Hyperalgesia is an increased sensitivity to normally painfulstimuli. Primary hyperalgesia occurs immediately within the area of theinjury. Secondary hyperalgesia occurs in the undamaged area surroundingthe injury. Examples of chronic pain include complex regional painsyndrome, pain arising from peripheral neuropathies, post-operativepain, chronic fatigue syndrome pain, tension-type headache, pain arisingfrom mechanical nerve injury and severe pain associated with diseasessuch as cancer, metabolic disease, neurotropic viral disease,neurotoxicity, inflammation, multiple sclerosis or any pain arising as aconsequence of or associated with stress or depressive illness.

Although opioids are cheap and effective, serious and potentiallylife-threatening side effects occur with their use, most notablyrespiratory depression and muscle rigidity. In addition the doses ofopioids which can be administered are limited by nausea, emesis,constipation, pruritis and urinary retention, often resulting inpatients electing to receive suboptimal pain control rather than sufferthese distressing side-effects. Furthermore, these side-effects oftenresult in patients requiring extended hospitalisation. Opioids arehighly addictive and are scheduled drugs in many territories.

The compounds of formula (I) are particularly useful in the treatment ofschizophrenia, bipolar disorder, depression including unipolardepression, seasonal depression and postpartum depression, premenstrualsyndrome (PMS) and premenstrual dysphoric disorder (PDD), learningdisorders, pervasive developmental disorder including autistic disorder,attention deficit disorders including Attention-Deficit/HyperactivityDisorder, tic disorders including Tourette's disorder, anxiety disordersincluding phobia and post traumatic stress disorder, cognitive disordersassociated with dementia, AIDS dementia, Alzheimer's, Parkinson's,Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus andhearing impairment and loss are of particular importance.

Particular cognitive disorders are dementia, delirium, amnesticdisorders and cognitive impartment including age-related cognitivedecline.

Particular anxiety disorders are generalized anxiety disorder,obsessive-compulsive disorder and panic attack.

Particular schizophrenia or psychosis pathologies are paranoid,disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder.

Particular neurologic disorders that can be treated with the compoundsof the formula (I) include in particular a cognitive disorder such asdementia, cognitive impairment, attention deficit hyperactivitydisorder.

Particular psychiatric disorders that can be treated with the compoundsof the formula (I) include in particular an anxiety disorder, a mooddisorder such as depression or a bipolar disorder, schizophrenia, apsychotic disorder.

Within the context of the treatment, the use according to the inventionof the compounds of the formula (I) involves a method. In this method,an effective quantity of one or more compounds or the formula (I), as arule formulated in accordance with pharmaceutical and veterinarypractice, is administered to the individual to be treated, preferably amammal, in particular a human being. Whether such a treatment isindicated, and in which form it is to take place, depends on theindividual case and is subject to medical assessment (diagnosis) whichtakes into consideration signs, symptoms and/or malfunctions which arepresent, the risks of developing particular signs, symptoms and/ormalfunctions, and other factors.

As a rule, the treatment is effected by means of single or repeateddaily administration, where appropriate together, or alternating, withother drugs or drug-containing preparations.

The invention also relates to the manufacture of pharmaceuticalcompositions for treating an individual, preferably a mammal, inparticular a human being. Thus, the compounds of the formula (I) arecustomarily administered in the form of pharmaceutical compositionswhich comprise an inert carrier (e.g. a pharmaceutically acceptableexcipient) together with at least one compound according to theinvention and, where appropriate, other drugs. These compositions can,for example, be administered orally, rectally, transdermally,subcutaneously, intravenously, intramuscularly or intranasally.

Examples of suitable pharmaceutical formulations are solid medicinalforms, such as powders, granules, tablets, in particular film tablets,lozenges, sachets, cachets, sugarcoated tablets, capsules, such as hardgelatin capsules and soft gelatin capsules, suppositories or vaginalmedicinal forms, semisolid medicinal forms, such as ointments, creams,hydrogels, pastes or plasters, and also liquid medicinal forms, such assolutions, emulsions, in particular oil-in-water emulsions, suspensions,for example lotions, injection preparations and infusion preparations,and eyedrops and eardrops. Implanted release devices can also be usedfor administering inhibitors according to the invention. In addition, itis also possible to use liposomes or microspheres.

When producing the compositions, the compounds according to theinvention are optionally mixed or diluted with one or more carriers(excipients). Carriers (excipients) can be solid, semisolid or liquidmaterials which serve as vehicles, carriers or medium for the activecompound.

Suitable carriers (excipients) are listed in the specialist medicinalmonographs. In addition, the formulations can comprise pharmaceuticallyacceptable auxiliary substances, such as wetting agents; emulsifying andsuspending agents; preservatives; antioxidants; anti-irritants;chelating agents; coating auxiliaries; emulsion stabilizers; filmformers; gel formers; odor masking agents; taste corrigents; resin;hydrocolloids; solvents; solubilizers; neutralizing agents; diffusionaccelerators; pigments; quaternary ammonium compounds; refatting andoverfatting agents; raw materials for ointments, creams or oils;silicone derivatives; spreading auxiliaries; stabilizers; sterilants;suppository bases; tablet auxiliaries, such as binders, fillers,glidants, disintegrants or coatings; propellants; drying agents;opacifiers; thickeners; waxes; plasticizers and white mineral oils. Aformulation in this regard is based on specialist knowledge asdescribed, for example, in Fiedler, H. P., Lexikon der Hilfsstoffe fürPharmazie, Kosmetik and angrenzende Gebiete [Encyclopedia of auxiliarysubstances for pharmacy, cosmetics and related fields], 4^(th) edition,Aulendorf: ECV-Editio-Cantor-Verlag, 1996.

The compounds of formula (I) may also be suitable for combination withother therapeutic agents.

Thus, the present invention also provides:

i) a combination comprising a compound of formula (I) with one or morefurther therapeutic agents;

ii) a pharmaceutical composition comprising a combination product asdefined in i) above and at least one carrier, diluent or excipient;

iii) the use of a combination as defined in i) above in the manufactureof a medicament for treating or preventing a disorder, disease orcondition as defined herein;

iv) a combination as defined in i) above for use in treating orpreventing a disorder, disease or condition as defined herein;

v) a kit-of-parts for use in the treatment of a disorder, disease orcondition as defined herein, comprising a first dosage form comprising acompound of formula (I) and one or more further dosage forms eachcomprising one or more further therapeutic agents for simultaneoustherapeutic administration,vi) a combination as defined in i) above for use in therapy;

vii) a method of treatment or prevention of a disorder, disease orcondition as defined herein comprising administering an effective amountof a combination as defined in i) above;

viii) a combination as defined in i) above for treating or preventing adisorder, disease or condition as defined herein.

The combination therapies of the invention may be administeredadjunctively. By adjunctive administration is meant the coterminous oroverlapping administration of each of the components in the form ofseparate pharmaceutical compositions or devices. This regime oftherapeutic administration of two or more therapeutic agents is referredto generally by those skilled in the art and herein as adjunctivetherapeutic administration; it is also known as add-on therapeuticadministration. Any and all treatment regimes in which a patientreceives separate but coterminous or overlapping therapeuticadministration of the compounds of formula (I) and at least one furthertherapeutic agent are within the scope of the current invention. In oneembodiment of adjunctive therapeutic administration as described herein,a patient is typically stabilized on a therapeutic administration of oneor more of the components for a period of time and then receivesadministration of another component.

The combination therapies of the invention may also be administeredsimultaneously. By simultaneous administration is meant a treatmentregime wherein the individual components are administered together,either in the form of a single pharmaceutical composition or devicecomprising or containing both components, or as separate compositions ordevices, each comprising one of the components, administeredsimultaneously. Such combinations of the separate individual componentsfor simultaneous combination may be provided in the form of akit-of-parts.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of compoundsof formula (I) to a patient receiving therapeutic administration of atleast one antipsychotic agent. In a further aspect, the inventionprovides the use of compounds of formula (I) in the manufacture of amedicament for adjunctive therapeutic administration for the treatmentof a psychotic disorder in a patient receiving therapeuticadministration of at least one antipsychotic agent. The inventionfurther provides compounds of formula (I) for use for adjunctivetherapeutic administration for the treatment of a psychotic disorder ina patient receiving therapeutic administration of at least oneantipsychotic agent.

In a further aspect, the invention provides a method of treatment of apsychotic disorder by adjunctive therapeutic administration of at leastone antipsychotic agent to a patient receiving therapeuticadministration of compounds of formula (I). In a further aspect, theinvention provides the use of at least one antipsychotic agent in themanufacture of a medicament for adjunctive therapeutic administrationfor the treatment of a psychotic disorder in a patient receivingtherapeutic administration of compounds of formula (I). The inventionfurther provides at least one antipsychotic agent for adjunctivetherapeutic administration for the treatment of a psychotic disorder ina patient receiving therapeutic administration of compounds of formula(I).

In a further aspect, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration ofcompounds of formula (I) in combination with at least one antipsychoticagent. The invention further provides the use of a combination ofcompounds of formula (I) and at least one antipsychotic agent in themanufacture of a medicament for simultaneous therapeutic administrationin the treatment of a psychotic disorder. The invention further providesa combination of compounds of formula (I) and at least one antipsychoticagent for simultaneous therapeutic administration in the treatment of apsychotic disorder. The invention further provides the use of compoundsof formula (I) in the manufacture of a medicament for simultaneoustherapeutic administration with at least one antipsychotic agent in thetreatment of a psychotic disorder. The invention further providescompounds of formula (I) for use for simultaneous therapeuticadministration with at least one antipsychotic agent in the treatment ofa psychotic disorder. The invention further provides the use of at leastone antipsychotic agent in the manufacture of a medicament forsimultaneous therapeutic administration with compounds of formula (I) inthe treatment of a psychotic disorder. The invention further provides atleast one antipsychotic agent for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of apsychotic disorder.

In further aspects, the invention provides a method of treatment of apsychotic disorder by simultaneous therapeutic administration of apharmaceutical composition comprising compounds of formula (I) and atleast one mood stabilising or antimanic agent, a pharmaceuticalcomposition comprising compounds of formula (I) and at least one moodstabilising or antimanic agent, the use of a pharmaceutical compositioncomprising compounds of formula (I) and at least one mood stabilising orantimanic agent in the manufacture of a medicament for the treatment ofa psychotic disorder, and a pharmaceutical composition comprisingcompounds of formula (I) and at least one mood stabilising or antimanicagent for use in the treatment of a psychotic disorder.

Antipsychotic agents include both typical and atypical antipsychoticdrugs. Examples of antipsychotic drugs that are useful in the presentinvention include, but are not limited to: butyrophenones, such ashaloperidol, pimozide, and droperidol; phenothiazines, such aschlorpromazine, thioridazine, mesoridazine, trifluoperazine,perphenazine, fluphenazine, thiflupromazine, prochlorperazine, andacetophenazine; thioxanthenes, such as thiothixene and chlorprothixene;thienobenzodiazepines; dibenzodiazepines; benzisoxazoles;dibenzothiazepines; imidazolidinones; benziso-thiazolyl-piperazines;triazine such as lamotrigine; dibenzoxazepines, such as loxapine;dihydroindolones, such as molindone; aripiprazole; and derivativesthereof that have antipsychotic activity.

Examples of tradenames and suppliers of selected antipsychotic drugs areas follows: clozapine (available under the tradename CLOZARIL®, fromMylan, Zenith Goldline, UDL, Novartis); olanzapine (available under thetradename ZYPREX®, from Lilly); ziprasidone (available under thetradename GEODON®, from Pfizer); risperidone (available under thetradename RISPERDAL®, from Janssen); quetiapine fumarate (availableunder the tradename SEROQUEL®, from AstraZeneca); haloperidol (availableunder the tradename HALDOL®, from Ortho-McNeil); chlorpromazine(available under the tradename THORAZINE®, from SmithKline Beecham(GSK)); fluphenazine (available under the tradename PROLIXIN®, fromApothecon, Copley, Schering, Teva, and American Pharmaceutical Partners,Pasadena); thiothixene (available under the tradename NAVANE®, fromPfizer); trifluoperazine(10-[3-(4-methyl-1-piperazinyl)propyl]-2-(trifluoromethyl)phenothiazinedihydrochloride, available under the tradename STELAZINE®, from SmithKlein Beckman); perphenazine (available under the tradename TRILAFON®;from Schering); thioridazine (available under the tradename MELLARIL®;from Novartis, Roxane, HiTech, Teva, and Alpharma); molindone (availableunder the tradename MOBAN®, from Endo); and loxapine (available underthe tradename LOXITANE (D; from Watson). Furthermore, benperidol(Glianimon®), perazine (Taxilan®) or melperone (Eunerpan®) may be used.Other antipsychotic drugs include promazine (available under thetradename SPARINE®), triflurpromazine (available under the tradenameVESPRI N®), chlorprothixene (available under the tradename TARACTAN®),droperidol (available under the tradename INAPSINE®), acetophenazine(available under the tradename TINDAL®), prochlorperazine (availableunder the tradename COMPAZINE®), methotrimeprazine (available under thetradename NOZINAN®), pipotiazine (available under the tradenamePIPOTRIL®), ziprasidone, and hoperidone.

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by adjunctivetherapeutic administration of compounds of formula (I) to a patientreceiving therapeutic administration of at least one agent suitable forthe treatment of a neurodegenerative disorder such as Alzheimer Disease.In a further aspect, the invention provides the use of compounds offormula (I) in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides compounds of formula (I) for use for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease.

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by adjunctivetherapeutic administration of at least one agent suitable for thetreatment of a neurodegenerative disorder such as Alzheimer Disease to apatient receiving therapeutic administration of compounds of formula(I). In a further aspect, the invention provides the use of at least oneagent suitable for the treatment of a neurodegenerative disorder such asAlzheimer Disease in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of compounds of formula (I). The invention furtherprovides at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease for adjunctivetherapeutic administration for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in a patient receiving therapeuticadministration of compounds of formula (I).

In a further aspect, the invention provides a method of treatment of aneurodegenerative disorder such as Alzheimer Disease by simultaneoustherapeutic administration of compounds of formula (I) in combinationwith at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides the use of a combination of compounds of formula (I)and at least one agent suitable for the treatment of a neurodegenerativedisorder such as Alzheimer Disease in the manufacture of a medicamentfor simultaneous therapeutic administration in the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides a combination of compounds of formula (I) and at leastone agent suitable for the treatment of a neurodegenerative disordersuch as Alzheimer Disease for simultaneous therapeutic administration inthe treatment of a neurodegenerative disorder such as Alzheimer Disease.The invention further provides the use of compounds of formula (I) inthe manufacture of a medicament for simultaneous therapeuticadministration with at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease in the treatment ofa neurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides compounds of formula (I) for use for simultaneoustherapeutic administration with at least one agent suitable for thetreatment of a neurodegenerative disorder such as Alzheimer Disease inthe treatment of a neurodegenerative disorder such as Alzheimer Disease.The invention further provides the use of at least one agent suitablefor the treatment of a neurodegenerative disorder such as AlzheimerDisease in the manufacture of a medicament for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of aneurodegenerative disorder such as Alzheimer Disease. The inventionfurther provides at least one agent suitable for the treatment of aneurodegenerative disorder such as Alzheimer Disease for simultaneoustherapeutic administration with compounds of formula (I) in thetreatment of a neurodegenerative disorder such as Alzheimer Disease.

Examples of agents suitable for the treatment of a neurodegenerativedisorder such as Alzheimer Disease that are useful in the presentinvention include, but are not limited to: cholinesterase inhibitors,agents targeting nicotinic or muscarinic acethylcholine receptors, NMDAreceptors, amyloid formation, mitochondrial dysfunctions, diseaseassociated calpain activity, neuroinflamation, tumor necrosis factorreceptors, NF-kappaB, peroxisome proliferator activator receptor gamma,Apolipoprotein E variant 4 (ApoE4), disease-associated increase of theHPA axis, epileptic discharges, vascular dysfunction, vascular riskfactors, and oxidative stress.

Suitable cholinesterase inhibitors which may be used in combination withthe compounds of the inventions include for example tacrine, donepezil,galantamine and rivastigmine.

Suitable NMDA receptors targeting agents which may be used incombination with the compounds of the inventions include for examplememantine.

Suitable agents affecting increased HPA axis activity which may be usedin combination with the compounds of the inventions include for exampleCRF1 antagonists or V1b antagonists.

In a further aspect therefore, the invention provides a method oftreatment of pain by adjunctive therapeutic administration of compoundsof formula (I) to a patient receiving therapeutic administration of atleast one agent suitable for the treatment of pain. In a further aspect,the invention provides the use of compounds of formula (I) in themanufacture of a medicament for adjunctive therapeutic administrationfor the treatment of pain in a patient receiving therapeuticadministration of at least one agent suitable for the treatment of pain.The invention further provides compounds of formula (I) for use foradjunctive therapeutic administration for the treatment of pain in apatient receiving therapeutic administration of at least one agentsuitable for the treatment of pain.

In a further aspect, the invention provides a method of treatment ofpain by adjunctive therapeutic administration of at least one agentsuitable for the treatment of pain to a patient receiving therapeuticadministration of compounds of formula (I). In a further aspect, theinvention provides the use of at least one agent suitable for thetreatment of pain in the manufacture of a medicament for adjunctivetherapeutic administration for the treatment of pain in a patientreceiving therapeutic administration of compounds of formula (I). Theinvention further provides at least one agent suitable for the treatmentof pain for adjunctive therapeutic administration for the treatment ofpain in a patient receiving therapeutic administration of compounds offormula (I).

In a further aspect, the invention provides a method of treatment ofpain by simultaneous therapeutic administration of compounds of formula(I) in combination with at least one agent suitable for the treatment ofpain. The invention further provides the use of a combination ofcompounds of formula (I) and at least one agent suitable for thetreatment of pain in the manufacture of a medicament for simultaneoustherapeutic administration in the treatment of pain. The inventionfurther provides a combination of compounds of formula (I) and at leastone agent suitable for the treatment of pain for simultaneoustherapeutic administration in the treatment of pain. The inventionfurther provides the use of compounds of formula (I) in the manufactureof a medicament for simultaneous therapeutic administration with atleast one agent suitable for the treatment of pain in the treatment ofpain. The invention further provides compounds of formula (I) for usefor simultaneous therapeutic administration with at least one agentsuitable for the treatment of pain in the treatment of pain. Theinvention further provides the use of at least one agent suitable forthe treatment of pain in the manufacture of a medicament forsimultaneous therapeutic administration with compounds of formula (I) inthe treatment of pain. The invention further provides at least one agentsuitable for the treatment of pain for simultaneous therapeuticadministration with compounds of formula (I) in the treatment of pain.

Examples of agents suitable for the treatment of pain that are useful inthe present invention include, but are not limited to: NSAIDs(Nonsteroidal Antiinflammatory Drugs), anticonvulsant drugs such ascarbamazepine and gabapentin, sodium channel blockers, antidepressantdrugs, cannabinoids and local anaesthetics.

Suitable agents used in combination with the compounds of the inventionsinclude for example celecoxib, etoricoxib, lumiracoxib, paracetamol,tramadol, methadone, venlafaxine, imipramine, duloxetine, bupropion,gabapentin, pregabalin, lamotrigine, fentanyl, parecoxib, nefopam,remifentanil, pethidine, diclofenac, rofecoxib, nalbuphine, sufentanil,pethidine, diamorphine and butorphanol.

It will be appreciated by those skilled in the art that the compoundsaccording to the invention may advantageously be used in conjunctionwith one or more other therapeutic agents, for instance, antidepressantagents such as 5HT3 antagonists, serotonin agonists, NK-1 antagonists,selective serotonin reuptake inhibitors (SSRI), noradrenaline re-uptakeinhibitors (SNRI), tricyclic antidepressants, dopaminergicantidepressants, H3 antagonists, 5HT1A antagonists, 5HT1 B antagonists,5HT1 D antagonists, D1 agonists, M1 agonists and/or anticonvulsantagents, as well as cognitive enhancers.

Suitable 5HT3 antagonists which may be used in combination of thecompounds of the inventions include for example ondansetron,granisetron, metoclopramide.

Suitable serotonin agonists which may be used in combination with thecompounds of the invention include sumatriptan, rauwolscine, yohimbine,metoclopramide.

Suitable SSRIs which may be used in combination with the compounds ofthe invention include fluoxetine, citalopram, femoxetine, fluvoxamine,paroxetine, indalpine, sertraline, zimeldine.

Suitable SNRIs which may be used in combination with the compounds ofthe invention include venlafaxine and reboxetine.

Suitable tricyclic antidepressants which may be used in combination witha compound of the invention include imipramine, amitriptiline,chlomipramine and nortriptiline.

Suitable dopaminergic antidepressants which may be used in combinationwith a compound of the invention include bupropion and amineptine.

Suitable anticonvulsant agents which may be used in combination of thecompounds of the invention include for example divalproex, carbamazepineand diazepam.

The following examples serve to explain the invention without limitingit.

The compounds were characterized by mass spectrometry, generallyrecorded via HPLC-MS in a fast gradient on C18-material(electrospray-ionisation (ESI) mode).

PREPARATION EXAMPLES

The following compounds were obtained using the procedures describedherein and in WO 2010/092180 (which is incorporated herein in itsentirety by reference).

Example 1N-[2-(3-benzyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-1H-imidazole-4-sulfonamide

1.1 5-Methoxyisoindolin-1-one

Methanol (53 mL) and NEt₃ (6.90 mL, 49.5 mmol) were added to2-bromo-5-methoxybenzonitrile (5.25 g, 24.76 mmol) and Pd-dppf (Heraeus)(0.362 g, 0.495 mmol) in a pressure tube. The mixture was stirred under60 psi of Carbon Monoxide at 80° C. for 8 hr. HPLC analysis (startingmaterial retention time 3.24 min., product retention time 2.82 min.)indicated clean and complete conversion. The obtained solution wasconcentrated down to a light orange color solid, 6.66 g.

ESI-MS [M+H⁺]=164.1 Calculated for C₉H₉NO₂=163.06.

1.2 tert-Butyl 5-methoxy-1-oxoisoindoline-2-carboxylate

To a round bottom flask were added 5-methoxyisoindolin-1-one (4.69 g,22.99 mmol) and dichloromethane (50 mL), then added4-dimethylaminopyridine (0.56 g, 4.6 mmol), di-tert-butyl dicarbonate(10.04 g, 46 mmol) and NEt₃ (4.65 g, 46 mmol) respectively. The reactionmixture was stirred at room temperature overnight. Water (30 mL) wasadded to the reaction mixture, this was separated. The aqueous layer wasextracted with dichloromethane two more times. The combined organiclayer was washed 1× with saturated NaCl solution. The organic phase wasdried on Na₂SO₄ and the solvent was evaporated. The residue was purifiedby flash-chromatography on silica gel with 25-50% ethyl acetate inhexane, 1.91 g (7.25 mmol, 32%) of the product was obtained.

ESI-MS [M+H⁺]=264.2 Calculated for C₁₄H₁₇NO₄=263.29

1.3 tert-Butyl 3-benzyl-5-methoxy-1-oxoisoindoline-2-carboxylate

Lithium bis(trimethysilyl)amide (4.8 mL, 4.8 mmol, 1 M in THF) was addedto a solution of the tert-butyl 5-methoxy-1-oxoisoindoline-2-carboxylate(0.975 g) in THF (7 mL) at −78° C. After stirring the solution at −78°C. for 1 hr, benzyl bromide (0.88 mL, 7.41 mmol) was added, this wasstirred at −78° C. for 1.5 hours. LC/MS showed complete conversion.Quenched the reaction mixture with saturated NaCl solution, thenextracted with ethyl acetate, the combined organic layer was washed 1×with saturated NaCl solution. The organic phase was dried on Na₂SO₄ andthe solvent was evaporated. The residue was purified byflash-chromatography on silica gel with 25-40% ethyl acetate in hexane,0.92 g (2.59 mmol, 70%) of the product was obtained.

ESI-MS [M+H⁺]=354 Calculated for C₂₁H₂₃NO₄=353.41

1.4 3-Benzyl-5-hydroxyisoindolin-1-one

To a stirred and cold (−5° C.-1-10° C.) solution of tert-butyl3-benzyl-5-methoxy-1-oxoisoindoline-2-carboxylate (0.92 g, 2.59 mmol) indichloromethane (9 mL) was added BBr₃ (7.8 mL, 7.78 mmol) dropwise underN₂. This was stirred at −5° C. for 3 hours, then room temperature forovernight. TLC showed complete conversion. The reaction mixture waspoured into ice-water, extracted 3× with dichloromethane. The combinedorganic layer was washed 1× with water, 1× with saturated NaHCO₃, 1×with saturated NaCl solution, dried over Na₂SO₄, concentrated down to alight yellow solid (620 mg, 100%).

ESI-MS [M+H⁺]=240.1 Calculated for C15H13NO2=239.09

1.5 tert-Butyl 2-(3-benzyl-1-oxoisoindolin-5-yloxy)ethylcarbamate

A mixture of 3-benzyl-5-hydroxyisoindolin-1-one (360 mg, 1.51 mmol),CsCO₃ (980 mg, 3.01 mmol) and tert-butyl 2-bromoethylcarbamate (506 mg,2.26 mmol) in 4 mL of acetonitrile was heated up to 80° C. for 4 hours,TLC showed complete conversion. The solvent was evaporated and theresidue was dissolved in ethyl acetate, then water was added, this wasseparated. The organic phase was dried on Na₂SO₄ and the solvent wasevaporated. The residue was purified by flash-chromatography on silicagel with 100% ethyl acetate, 426 mg (1.11 mmol, 74%) of the product wasobtained.

ESI-MS [M+H⁺]=382.9 Calculated for C₂₂H₂₆N₂O₄=382.19

1.6 5-(2-Aminoethoxy)-3-benzylisoindolin-1-one hydrochloride

To tert-butyl 2-(3-benzyl-1-oxoisoindolin-5-yloxy)ethylcarbamate (426mg, 1.11 mmol) was added 3 mL of dioxane and 3 mL of 4N HCl in dioxaneat room temperature, this was stirred for 3 hours, then concentrateddown to give 5-(2-aminoethoxy)-3-benzylisoindolin-1-one hydrochloride asHCl salt (355 mg, 100%).

ESI-MS [M+H⁺]=282.3 Calculated for C₁₇H₁₈N₂O₂=282.14

1.7N-(2-(3-Benzyl-1-oxoisoindolin-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide

To 5-(2-aminoethoxy)-3-benzylisoindolin-1-one hydrochloride (200 mg,0.627 mmol) in 3 mL of dichloromethane was added NEt₃ (0.3 mL, 2.2 mmol)and 4-dimethylaminopyridine (7.7 mg, 0.063 mmol) and1-methyl-1H-imidazole-4-sulfonyl chloride (125 mg, 0.69 mmol).

The reaction mixture was stirred at room temperature for 2 hours. Thesolvent was evaporated and the residue was triturated with ethyl acetatefirst, then triturated with water to giveN-(2-(3-benzyl-1-oxoisoindolin-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamideas a white solid (211 mg, 79%).

ESI-MS [M+H⁺]=427.1 Calculated for C₂₁H₂₂N₄O₄S=426.14

Example 2N-[(3-Benzyl-1-oxo-isoindolin-5-yl)methyl]-1-methyl-1H-imidazole-4-sulfonamide

2.1 3-Benzyl-1-oxoisoindolin-5-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate

To a solution of nonafluorobutanesulfonyl fluoride (712 mg, 2.36 mmol)and NEt₃ (0.49 mL, 3.54 mmol) in 3 mL of dichloromethane was added3-benzyl-5-hydroxyisoindolin-1-one (example 1.4, 282 mg, 1.18 mmol) in 2mL of dichloromethane slowly. This reaction mixture was stirred at roomtemperature for overnight. TLC showed complete conversion, the solventwas evaporated. The residue was purified by flash-chromatography onsilica gel with 30-80% ethyl acetate in hexane, 474 mg (77%) of theproduct was obtained.

ESI-MS [M+H⁺]=522.0 Calculated for C₁₃H₁₂F₃NO₄S=521.03

2.2 3-Benzyl-1-oxoisoindoline-5-carbonitrile

To a round bottom flask was added 12 mL of DMF. This was degassed withN₂ for 10 min and then added 3-benzyl-1-oxoisoindolin-5-yl1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (609 mg, 1.17 mmol),tris(dibenzylideneacetone)dipalladium(0) (214 mg, 0.23 mmol),1,1′-bis(diphenylphosphino)ferrocene (142 mg, 0.26 mmol) and zinc (30.6mg, 0.47 mmol) respectively. This was heated up to 100° C. for 15 minunder N₂, then added Zinc cyanide (82 mg, 0.70 mmol). This was heated at100° C. for 2.5 hours, LC/MS showed complete conversion. The reactionmixture was cooled down to room temperature, diluted with ethyl acetate,then filtered through a pad of celite, the filtrate was concentrateddown and the residue was purified by flash-chromatography on silica gelwith 30-90% ethyl acetate in hexane, 125 mg (43%) of the product wasobtained.

ESI-MS [M−H⁺]=247.1 Calculated for C₁₆H₁₂N₂O=248.09

2.3 5-(Aminomethyl)-3-benzylisoindolin-1-one

To a solution of 3-benzyl-1-oxoisoindoline-5-carbonitrile (190 mg, 0.77mmol) in MeOH (4 mL) was added cobalt(II) chloride hexahydrate (364 mg,1.53 mmol), then added NaBH₄(232 mg, 6.12 mmol) in portions carefullywithin 45 min. The reaction mixture was stirred at room temperature for30 min, TLC showed complete conversion. Carefully quenched reaction byadding concentrated HCl until the black precipitates dissolved. Thereaction mixture was basified with concentrated NH₄OH until pH=8-9, abrown colour slurry was obtained, diluted with ethyl acetate. This wasfiltered, for filtrate, washed 1× with water. The organic phase wasdried on Na₂SO₄ and the solvent was evaporated. The residue was purifiedby flash-chromatography on silica gel with 5-10% MeOH in dichloromethane(0.5% NEt₃ added), 80 mg (41%) of the product was obtained.

ESI-MS [M+H⁺]=253.1 Calculated for C₁₆H₁₆N₂O=252.13

2.4N-((3-Benzyl-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamide

The title compound was prepared using the same sequence of steps asdescribed in example 1.7 by substituting5-(aminomethyl)-3-benzylisoindolin-1-one for5-(2-aminoethoxy)-3-benzylisoindolin-1-one hydrochloride. 77.4 mg (62%)of the product was obtained.

ESI-MS [M+H⁺]=397.0 Calculated for C₂₀H₂₀N₄O₃S=396.13

Example 3[2-(3-Benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-carbamic acidtert-butyl ester

ESI-MS [M+H⁺]=383 Calculated for C₂₂H₂₆N₂O₄=382

Example 4N-[(3-Benzylisoindolin-5-yl)methyl]-1-methyl-1H-imidazole-4-sulfonamide

The title compound was prepared using the same sequence of steps asdescribed in example 5 by substitutingN-(2-(3-benzyl-1-oxoisoindolin-5-yl)methyl)-1-methyl-1H-imidazole-4-sulfonamideforN-(2-(3-benzyl-1-oxoisoindolin-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide.1.8 mg (2.7%) of the product was obtained.

ESI-MS [M+H⁺]=383.0 Calculated for C₂₀H₂₂N₄O₂S=382.15

Example 5N-[2-(3-Benzylisoindolin-5-yl)oxyethyl]-1-methyl-1H-imidazole-4-sulfonamide

To a solution ofN-(2-(3-benzyl-1-oxoisoindolin-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide(example 1.7, 111 mg, 0.26 mmol) in dry THF (1.6 mL) was added boranedimethyl sulfide complex (0.78 mL, 1.56 mmol, 2M in THF) under N₂. Thereaction mixture was heated up to 65° C. for 7 hours, then stirred atroom temperature for overnight. Quenched reaction by carefully additionof 0.5 N HCl (0.5 mL) solution and the mixture was refluxed for 2 hours,then basified the reaction mixture with 1N NaOH aqueous to pH=8-9,extracted 2× with ethyl acetate, this was separated. The organic phasewas dried on Na₂SO₄ and the solvent was evaporated. The residue waspurified by flash-chromatography on silica gel with 5-10% MeOH in DCM(0.5% NEt₃ added), 22.2 mg (21%) of the product was obtained.

ESI-MS [M+H⁺]=413.1 Calculated for C₂₁H₂₄N₄O₃S=412.16

Example 6N-[2-(3-Benzyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-1H-pyrazole-4-sulfonamide

ESI-MS [M+H⁺]=427 Calculated for C₂₁H₂₂N₄O₄S=426

Example 7N-[2-(3-Benzylisoindolin-5-yl)oxyethyl]-1-methyl-1H-pyrazole-4-sulfonamide

ESI-MS [M+H⁺]=413 Calculated for C₂₁H₂₄N₄O₃S=412

Example 8N-[2-(3-Benzyl-3-methyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-1H-imidazole-4-sulfonamide

ESI-MS [M+H⁺]=441 Calculated for C₂₂H₂₄N₄O₄S=440

Example 9N-[2-(3-Benzyl-3-methyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-1H-pyrazole-4-sulfonamide

9.1 tert-Butyl1-benzyl-6-methoxy-1-methyl-3-oxoisoindoline-2-carboxylate

Lithium bis(trimethysilyl)amide (5.04 mL, 5.04 mmol, 1 M in THF) wasadded to a solution of the tert-butyl3-benzyl-5-methoxy-1-oxoisoindoline-2-carboxylate (example 1.3, 890 mg,2.52 mmol) in THF (8 mL) at −78° C. After stirring the solution at −78°C. for 1 hr, iodomethane (465 mg, 3.27 mmol) was added, this was stirredat −78° C. for 1.5 hours. LC/MS showed complete conversion. Quenched thereaction mixture with saturated NaCl solution, then extracted with ethylacetate, the combined organic layer was washed 1× with saturated NaClsolution. The organic phase was dried on Na₂SO₄ and the solvent wasevaporated. The residue was purified by flash-chromatography on silicagel with 25-40% ethyl acetate in hexane, 750 mg (2.04 mmol, 81%) of theproduct was obtained.

ESI-MS [M+H⁺]=368.0 Calculated for C₂₂H₂₅NO₄=367.18

9.2 3-Benzyl-5-hydroxy-3-methylisoindolin-1-one

The title compound was prepared using the same sequence of steps asdescribed in example 1.4 by substituting tert-butyl1-benzyl-6-methoxy-1-methyl-3-oxoisoindoline-2-carboxylate fortert-butyl 3-benzyl-5-methoxy-1-oxoisoindoline-2-carboxylate. 530 mg(100%) of the product was obtained.

ESI-MS [M+H⁺]=254.13 Calculated for C₁₆H₁₅NO₂=253.29

9.3 tert-Butyl2-(3-benzyl-3-methyl-1-oxoisoindolin-5-yloxy)ethylcarbamate

The title compound was prepared using the same sequence of steps asdescribed in example 1.5 by substituting3-benzyl-5-hydroxy-3-methylisoindolin-1-one for3-benzyl-5-hydroxyisoindolin-1-one, 610 mg (73.5%) of the product wasobtained.

ESI-MS [M+H⁺]=397.1 Calculated for C₂₃H₂₈N₂O₄=396.20

9.4 5-(2-Aminoethoxy)-3-benzyl-3-methylisoindolin-1-one hydrochloride

The title compound was prepared using the same sequence of steps asdescribed in example 1.6 by substituting tert-butyl2-(3-benzyl-3-methyl-1-oxoisoindolin-5-yloxy)ethylcarbamate fortert-butyl 2-(3-benzyl-1-oxoisoindolin-5-yloxy)ethylcarbamate, 538 mg(100%) of the product was obtained.

ESI-MS [M+H⁺]=297.1 Calculated for C₁₈H₂₁ClN₂O₂=296.15

9.5N-(2-(3-Benzyl-3-methyl-1-oxoisoindolin-5-yloxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamide

The title compound was prepared using the same sequence of steps asdescribed in example 1.7 by substituting5-(2-aminoethoxy)-3-benzyl-3-methylisoindolin-1-one hydrochloride for5-(2-aminoethoxy)-3-benzylisoindolin-1-one hydrochloride, 112 mg (76%)of the product was obtained.

ESI-MS [M+H⁺]=441.2 Calculated for C₂₂H₂₄N₄O₄S=440.15

Example 10N-[2-(3-Benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-1H-pyrazole-4-sulfonamide

The title compound was prepared using the same sequence of steps asdescribed in example 5 by substitutingN-(2-(3-benzyl-3-methyl-1-oxoisoindolin-5-yloxy)ethyl)-1-methyl-1H-pyrazole-4-sulfonamideforN-(2-(3-benzyl-1-oxoisoindolin-5-yloxy)ethyl)-1-methyl-1H-imidazole-4-sulfonamide,41.5 mg (40%) of the product was obtained.

ESI-MS [M+H⁺]=427.1 Calculated for C₂₂H₂₆N₄O₃S=426.17

Example 11N-[2-(3-Benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide

ESI-MS [M+H⁺]=427 Calculated for C₂₂H₂₆N₄O₃S=426

Example 12N-[2-[3-Benzyl-2-(2,2,2-trifluoroacetyhisoindolin-5-yl]oxyethyl]-1-methyl-1H-pyrazole-4-sulfonamide

ESI-MS [M+H⁺]=509 Calculated for C₂₃H₂₃F₃N₄O₄S=509

Example 13N-[2-(3-Benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-1H-pyrazole-4-sulfonamide;2,2,2-trifluoroacetic acid

ESI-MS [M+H⁺]=427 Calculated for C₂₂H₂₆N₄O₃S=426

Example 14N-[2-(3-Benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-1H-imidazole-4-sulfonamide;2,2,2-trifluoroacetic acid

ESI-MS [M+H⁺]=427 Calculated for C₂₂H₂₆N₄O₃S=426

Example 15N-[2-[3-Benzyl-2-(2,2,2-trifluoroethyl)isoindolin-5-yl]oxyethyl]-1-methyl-1H-pyrazole-4-sulfonamide;2,2,2-trifluoroacetic acid

ESI-MS [M+H⁺]=495 Calculated for C₂₃H₂₅F₃N₄O₃S=494

Example 16N-[2-[3-Benzyl-2-(oxetan-3-yl)isoindolin-5-yl]oxyethyl]-1-methyl-1H-pyrazole-4-sulfonamide;2,2,2-trifluoroacetic acid

ESI-MS [M+H⁺]=469 Calculated for C₂₄H₂₈N₄O₄S=468

Example 17N-[2-(3-Benzyl-3-methyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-cyclopropyl-methanesulfonamide

ESI-MS [M+H⁺]=415 Calculated for C₂₂H₂₆N₂O₄S=414

Example 18N-[2-(3-Benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-cyclopropyl-methanesulfonamide;2,2,2-trifluoroacetic acid

ESI-MS [M+H⁺]=401 Calculated for C₂₂H₂₈N₂O₃S=400

Example 19N-[2-(3-Benzyl-6-fluoro-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-1H-imidazole-4-sulfonamide

ESI-MS [M+H⁺]=443 Calculated for C₂₁H₂₁FN₄O₄S=444

Example 20N-(2-(3-Benzyl-6-fluoro-2-methylisoindolin-5-yloxy)ethyl)-1-cyclopropyl-methanesulfonamide

ESI-MS [M+H⁺]=419 Calculated for C₂₂H₂₇FN₂O₃S=418

Example 21 1-Methyl-1H-imidazole-4-sulfonic acid[2-(3-benzyl-6-fluoro-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-amide

ESI-MS [M+H⁺]=430 Calculated for C₂₁H₂₃FN₄O₃S=431

Example 22N-[2-(3-Benzyl-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-C-cyclopropyl-methanesulfonamide

ESI-MS [M+H⁺]=418 Calculated for C₂₁H₂₃FN₂O₄S=419

Example 23N-[2-(3-Benzyl-6-fluoro-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-C-cyclopropyl-methanesulfonamide

ESI-MS [M+H⁺]=404 Calculated for C₂₁H₂₅FN₂O₃S=405

Example 24 Ethanesulfonic acid[2-(3-benzyl-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-amide

ESI-MS [M+H⁺]=392 Calculated for C₁₉H₂₁FN₂O₄S=393

Example 25 Ethanesulfonic acid[2-(3-benzyl-6-fluoro-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-amide

ESI-MS [M+H⁺]=378 Calculated for C₁₉H₂₃FN₂O₃S=379

Example 26N-(3-Benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-C-cyclopropyl-methanesulfonamide

ESI-MS [M+H⁺]=370 Calculated for C₂₀H₂₂N₂O₃S=371

Example 27 Ethanesulfonic acid(3-benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide

ESI-MS [M+H⁺]=344 Calculated for C₁₈H₂₀N₂O₃S=345

Example 28 Propane-1-sulfonic acid(3-benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide

ESI-MS [M+H⁺]=358 Calculated for C₁₉H₂₂N₂O₃S=359

Example 29N-(3-Benzyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-C-cyclopropyl-methanesulfonamide

ESI-MS [M+H⁺]=356 Calculated for C₂₀H₂₄N₂O₂S=357

Example 30 Ethanesulfonic acid(3-benzyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide

ESI-MS [M+H⁺]=330 Calculated for C₁₈H₂₂N₂O₂S=331

Example 31 Propane-1-sulfonic acid(3-benzyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide

ESI-MS [M+H⁺]=344 Calculated for C₁₉H₂₄N₂O₂S=345

Biological Testing

1. [³H]-Glycine Uptake into Recombinant CHO Cells Expressing HumanGlyT1:

Human GlyT1c expressing recombinant hGlyT1c_5_CHO cells were plated at20,000 cells per well in 96 well Cytostar-T scintillation microplates(Amersham Biosciences) and cultured to sub-confluency for 24 h. Forglycine uptake assays the culture medium was aspirated and the cellswere washed once with 100 μl HBSS (Gibco BRL, #14025-050) with 5 mML-Alanine (Merck #1007). 80 μl HBSS buffer were added, followed by 10 μlinhibitor or vehicle (10% DMSO) and 10 μl [³H]-glycine (TRK71, AmershamBiosciences) to a final concentration of 200 nM for initiation ofglycine uptake. The plates were placed in a Wallac Microbeta(PerkinElmer) and continuously counted by solid phase scintillationspectrometry during up to 3 hours. Nonspecific uptake was determined inthe presence of 10 μM Org24598. IC₅₀ calculations were made byfour-parametric logistic nonlinear regression analysis (GraphPad Prism)using determinations within the range of linear increase of [³H]-glycineincorporation between 60 and 120 min.

2. Radioligand Binding Assays Using Recombinant CHO Cell MembranesExpressing Human GlyT1:

Radioligand binding to human GlyT1c transporter-expressing membranes wasdetermined as described in Mezler et al., Molecular Pharmacology74:1705-1715, 2008.

The following results were obtained with the compounds disclosed in theexamples:

Example radioligand binding K_(iapp) [μmol] 1 <1 2 <1 3 >10 4 <1 5 <0.16 <10 7 <0.1 8 <10 9 <10 10 <0.1 11 <0.1 12 <1 13 <0.01 14 <0.1 15 <1 16<0.1 17 <10 18 <1 19 <1 20 <1 21 <0.1 22 <10 23 <1 24 <10 25 <10 26 <1028 <10 29 <10 30 <100 31 <103. Metabolic Stability

Metabolic stability was determined as follows:

0.5 μM test substance was preincubated together with human livermicrosomes (0.25 mg of microsomal protein/ml) in 0.05 M potassiumphosphate buffer of pH 7.4 in microtiter plates at 37° C. for 5 min. Thereaction was started by adding NADPH (1.0 mM). After 0, 5, 10, 15, 20and 30 min, 65 μl aliquots were removed, and the reaction wasimmediately stopped and cooled with twice the amount of ethanol. Thesamples were frozen until analyzed. The remaining concentration ofundegraded test substance was determined by LC MSMS. The half-life (T½)was determined from the gradient of the signal of test substance/unittime plot, allowing to calculate the half-life of the test substance,assuming first order kinetics, from the decrease in the concentration ofthe compound with time. The microsomal clearance (mCl) was calculatedfrom mCl=ln 2/T½/(content of microsomal protein in mg/ml)×1000 (modifiedfrom references: Di, The Society for Biomolecular Screening, 2003,453-462; Obach, DMD, 1999 vol 27. N 11, 1350-1359).

The following results were obtained with the compounds disclosed in theexamples:

Example human mCl [μl/min/mg] 5 <1 7 <10 4 <1

We claim:
 1. An isoindoline derivative of formula (I)

wherein R is R¹-W-A¹-Q-Y-A²-X¹- or —CN; R¹ is hydrogen, C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenated C₁-C₆-alkyl,tri-(C₁-C₄-alkyl)-silyl-C₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl,C₁-C₆-alkoxy-C₁-C₄-alkyl, amino-C₁-C₄-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkyloxycarbonylamino-C₁-C₄-alkyl,C₁-C₆-alkylaminocarbonylamino-C₁-C₄-alkyl,di-C₁-C₆-alkylaminocarbonylamino-C₁-C₄ alkyl,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkyl, (optionally substitutedC₆-C₁₂-aryl-C₁-C₆-alkyl)amino-C₁-C₄-alkyl, optionally substitutedC₆-C₁₂-aryl-C₁-C₄-alkyl, optionally substitutedC₃-C₁₂-heterocyclyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl, C₁-C₆-alkylcarbonyl,C₁-C₆-alkoxycarbonyl, halogenated C₁-C₆-alkoxycarbonyl,C₆-C₁₂-aryloxycarbonyl, aminocarbonyl, C₁-C₆-alkylaminocarbonyl,(halogenated C₁-C₄-alkyl)aminocarbonyl, C₆-C₁₂-arylaminocarbonyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionally substituted C₆-C₁₂-aryl,hydroxy, C₁-C₆-alkoxy, halogenated C₁-C₆-alkoxy, C₁-C₆-hydroxyalkoxy,C₁-C₆-alkoxy-C₁-C₄-alkoxy, amino-C₁-C₄-alkoxy,C₁-C₆-alkylamino-C₁-C₄-alkoxy, di-C₁-C₆-alkylamino-C₁-C₄-alkoxy,C₁-C₆-alkylcarbonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylcarbonylamino-C₁-C₄-alkoxy,C₁-C₆-alkoxycarbonylamino-C₁-C₄-alkoxy, C₆-C₁₂ aryl-C₁-C₄-alkoxy,C₁-C₆-alkylsulfonylamino-C₁-C₄-alkoxy, (halogenatedC₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₆-C₁₂-arylsulfonylamino-C₁-C₄-alkoxy, (C₆-C₁₂ aryl-C₁-C₆-alkyl)sulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclylsulfonylamino-C₁-C₄-alkoxy,C₃-C₁₂-heterocyclyl-C₁-C₄-alkoxy, C₆-C₁₂-aryloxy,C₃-C₁₂-heterocyclyloxy, C₁-C₆-alkylthio, halogenated C₁-C₆-alkylthio,C₁-C₆-alkylamino, (halogenated C₁-C₆-alkyl)amino, di-C₁-C₆-alkylamino,di-(halogenated C₁-C₆-alkyl)amino, C₁-C₆-alkylcarbonylamino,(halogenated C₁-C₆-alkyl)carbonylamino, C₆-C₁₂-arylcarbonylamino,C₁-C₆-alkylsulfonylamino, (halogenated C₁-C₆-alkyl)sulfonylamino,C₆-C₁₂-arylsulfonylamino or optionally substituted C₃-C₁₂-heterocyclyl;W is —NR⁸— or a bond; A¹ is optionally substituted C₁-C₄-alkylene or abond; Q is —S(O)₂— or —C(O)—; Y is —NR⁹— or a bond; A² is optionallysubstituted C₁-C₄-alkylene, C₁-C₄-alkylene-CO—, —CO—C₁-C₄-alkylene,C₁-C₄-alkylene-O—C₁-C₄-alkylene, C₁-C₄-alkylene-NR¹⁰—C₁-C₄-alkylene,optionally substituted C₂-C₄-alkenylene, optionally substitutedC₂-C₄-alkynylene, optionally substituted C₆-C₁₂-arylene, optionallysubstituted C₆-C₁₂-heteroarylene or a bond; X¹ is —O—, —NR¹¹—, —S—,optionally substituted C₁-C₄-alkylene, optionally substitutedC₂-C₄-alkenylene, or optionally substituted C₂-C₄-alkynylene, wherein-Y-A²-X¹- comprises at least 2, 3 or 4 atoms in the main chain; R² ishydrogen, halogen, C₁-C₆-alkyl, halogenated C₁-C₄-alkyl,hydroxy-C₁-C₄-alkyl, —CN, C₂-C₆-alkenyl, C₂-C₆-alkynyl, optionallysubstituted C₆-C₁₂-aryl, hydroxy, C₁-C₆-alkoxy, halogenatedC₁-C₆-alkoxy, C₁-C₆-alkoxycarbonyl, C₂-C₆-alkenyloxy,C₆-C₁₂-aryl-C₁-C₄-alkoxy, C₁-C₆-alkylcarbonyloxy, C₁-C₆-alkylthio,C₁-C₆-alkylsulfinyl, C₁-C₆-alkylsulfonyl, aminosulfonyl, amino,C₁-C₆-alkylamino, C₂-C₆-alkenylamino, nitro or optionally substitutedC₃-C₁₂-heterocyclyl, or two radicals R² together with the ring atoms ofA to which they are bound form a 5- or 6 membered ring; R³ is hydrogen,halogen, C₁-C₆-alkyl or C₁-C₆-alkoxy, or two radicals R³ together withthe carbon atom to which they are attached form a carbonyl group; R⁴ ishydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenatedC₁-C₄-alkyl, hydroxy-C₁-C₄-alkyl, C₁-C₆-alkoxy-C₁-C₄-alkyl,amino-C₁-C₄-alkyl, CH₂CN, C₆-C₁₂-aryl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl,—CHO, C₁-C₄-alkylcarbonyl, (halogenated C₁-C₄-alkyl)carbonyl,C₆-C₁₂-arylcarbonyl, C₁-C₄-alkoxycarbonyl, C₆-C₁₂-aryloxycarbonyl,C₁-C₆-alkylaminocarbonyl, C₂-C₆-alkenyl, —C(═NH)NH₂, —C(═NH)NHCN,C₁-C₆-alkylsulfonyl, C₆-C₁₂-arylsulfonyl, amino, —NO orC₃-C₁₂-heterocyclyl; X² is >CR^(12a)R^(12b); X³ is a bond; R⁵ isoptionally substituted C₆-C₁₂-aryl, optionally substitutedC₃-C₁₂-cycloalkyl, or optionally substituted C₃-C₁₂-heterocyclyl; R⁶ ishydrogen or C₁-C₆-alkyl; R⁷ is hydrogen or C₁-C₆-alkyl; R⁸ is hydrogenor C₁-C₆-alkyl; R⁹ is hydrogen, C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl,amino-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl-C₁-C₄-alkyl orC₃-C₁₂-heterocyclyl; or R⁹, R¹ together are C₁-C₄-alkylene; or R⁹ isC₁-C₄-alkylene that is bound to a carbon atom in A² and A² isC₁-C₄-alkylene or to a carbon atom in X¹ and X¹ is C₁-C₄-alkylene; R¹⁰is hydrogen, C₁-C₆-alkyl or C₁-C₆-alkylsulfonyl; R¹¹ is hydrogen orC₁-C₆-alkyl, or R⁹, R¹¹ together are C₁-C₄-alkylene, R^(12a) ishydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy; R^(12b) is hydrogen or C₁-C₆-alkyl, or R^(12a), R^(12b)together are optionally substituted C₁-C₄-alkylene, wherein one —CH₂— ofC₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁴—; R^(13a) ishydrogen, optionally substituted C₁-C₆-alkyl,C₁-C₆-alkylamino-C₁-C₄-alkyl, di-C₁-C₆-alkylamino-C₁-C₄-alkyl,C₃-C₁₂-heterocyclyl-C₁-C₆-alkyl, optionally substituted C₆-C₁₂-aryl orhydroxy; R^(13b) is hydrogen or C₁-C₆-alkyl, or R^(13a), R^(13b)together are optionally substituted C₁-C₄-alkylene, wherein one —CH₂- ofC₁-C₄-alkylene may be replaced by an oxygen atom or —NR¹⁵—; R¹⁴ ishydrogen or C₁-C₆-alkyl; and R¹⁵ is hydrogen or C₁-C₆-alkyl; or aphysiologically tolerated salt thereof.
 2. A compound as claimed inclaim 1, wherein R is R¹-W-A¹-Q-Y-A²-X¹-.
 3. A compound as claimed inclaim 1, wherein R¹ is C₁-C₆-alkyl, C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl, or optionally substituted C₃-C₁₂-heterocyclyl.
 4. Acompound as claimed in claim 1, wherein A¹ is a bond.
 5. A compound asclaimed in claim 1, wherein W is a bond and Y is a bond, or wherein W isa bond and Y is —NR⁹—.
 6. A compound as claimed in claim 1, wherein X¹is —O— and A² is C₁-C₄-alkylene, or X¹ is C₁-C₄-alkylene and A² is abond.
 7. A compound as claimed in claim 1, wherein R¹-W-A¹-Q-Y-A²-X¹- isR¹-S(O)₂-NR⁹-A²-X¹- or R¹—S(O)₂—X¹—.
 8. A compound as claimed in claim1, having formula


9. A compound as claimed in claim 1, wherein R² is hydrogen or halogen.10. A compound as claimed in claim 1, wherein R³ is hydrogen orC₁-C₆-alkyl, or two radicals R³ together with the carbon atom to whichthey are attached form a carbonyl group.
 11. A compound as claimed inclaim 1, wherein R⁴ is hydrogen, C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenated C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl, (halogenated C₁-C₄-alkyl)carbonyl, orC₃-C₁₂-heterocyclyl.
 12. A compound as claimed in claim 1, whereinR^(12a)is hydrogen or C₁-C₆-alkyl and R^(12b)is hydrogen or C₁-C₆-alkyl,or wherein R^(12a), R^(12b) together are optionally substitutedC₁-C₄-alkylene.
 13. A compound as claimed in claim 1, having formula

wherein R^(17a), R^(17b), R^(17c), R^(17d), R^(17e) independently arehydrogen, halogen, or halogenated C₁-C₆-alkyl, or having formula

wherein R^(17b), R^(17c), R^(17d), R^(17e) independently are hydrogen,halogen, or halogenated C₁-C₆-alkyl.
 14. A compound as claimed in claim1, wherein R is R¹-W-A¹-Q-Y-A²-X¹-; R¹ is C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, C₃-C₁₂-cycloalkyl, or optionallysubstituted C₃-C₁₂-heterocyclyl; W is a bond; A¹ is a bond; Q is—S(O)₂—; Y is —NR⁹- or a bond; A² is C₁-C₄-alkylene; X¹ is —O— orC₁-C₄-alkylene; R² is hydrogen or halogen; R³ is hydrogen orC₁-C₆-alkyl, or two radicals R³ together with the carbon atom to whichthey are attached form a carbonyl group; R⁴ is hydrogen, C₁-C₆-alkyl,C₃-C₁₂-cycloalkyl-C₁-C₄-alkyl, halogenated C₁-C₄-alkyl,C₃-C₁₂-cycloalkyl, (halogenated C₁-C₄-alkyl)carbonyl, orC₃-C₁₂-heterocyclyl; X² is CR^(12a)R^(12b); X³ is a bond; R⁵ isoptionally substituted phenyl; R⁹ is hydrogen; R^(12a) is hydrogen; andR^(12b) is hydrogen.
 15. A compound as claimed in claim 1 which is:N-[2-(3-benzyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;N-[(3-benzyl-1-oxo-isoindolin-5-yl)methyl]-1-methyl-imidazole-4-sulfonamide;[2-(3-Benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy) -ethyl]-carbamicacid tert-butyl ester;N-[(3-benzylisoindolin-5-yl)methyl]-1-methyl-imidazole-4-sulfonamide;N-[2-(3-benzylisoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;N-[2-(3-benzyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide;N-[2-(3-benzylisoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide;N-[2-(3-benzyl-3-methyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;N-[2-(3-benzyl-3-methyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-ethyl-pyrazole-4-sulfonamide;N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide;N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;N-[2-[3-benzyl-2-(2,2,2-trifluoroacetyl)isoindolin-5-yl]oxyethyl]-1-methyl-pyrazole-4-sulfonamide;N-[2-(3-benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamide;N-[2-(3-benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;N-[2-[3-benzyl-2-(2,2,2-trifluoroethyl)isoindolin-5-yl]oxyethyl]-1-methyl-pyrazole-4-sulfonamide;N-[2-[3-benzyl-2-(oxetan-3-yl)isoindolin-5-yl]oxyethyl]-1-methyl-pyrazole-4-sulfonamide;N-[2-(3-benzyl-3-methyl-1-oxo-isoindolin-5-yl)oxyethyl]-1-cyclopropyl-methanesulfonamide;N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-cyclopropyl-methanesulfonamide;N-[2-(3-benzyl-6-fluoro-1-oxo-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamide;N-(2-(3-benzyl-6-fluoro-2-methylisoindolin-5-yloxy)ethyl)-1-cyclopropyl-methanesulfonamide;1-Methyl-1H-imidazole-4-sulfonic acid[2-(3-benzyl-6-fluoro-2,3-dihydro-1H-isoindol-5-yloxy) -ethyl]-amide;N-[2-(3-Benzyl-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-C-cyclopropyl-methanesulfonamide;N-[2-(3-Benzyl-6-fluoro-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-C-cyclopropyl-methanesulfonamide;Ethanesulfonic acid[2-(3-benzyl-6-fluoro-1-oxo-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-amide; Ethanesulfonic acid[2-(3-benzyl-6-fluoro-2,3-dihydro-1H-isoindol-5-yloxy)-ethyl]-amide;N-(3-Benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-C-cyclopropyl-methanesulfonamide;Ethanesulfonic acid(3-benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide;Propane-1-sulfonic acid(3-benzyl-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide;N-(3-Benzyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-C-cyclopropyl-methanesulfonamide;Ethanesulfonic acid (3-benzyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide;or Propane-1-sulfonic acid(3-benzyl-2,3-dihydro-1H-isoindol-5-ylmethyl)-amide; or aphysiologically tolerated salt thereof.
 16. A pharmaceutical compositionwhich comprises a carrier and a compound of claim
 1. 17. A method fortreating a neurologic or psychiatric disorder or pain in a mammalianpatient in need thereof which comprises administering to the patient atherapeutically effective amount of a compound of claim 1, wherein theneurologic disorder is selected from the group consisting of dementia,cognitive impairment, and attention deficit disorder, and wherein thepsychiatric disorder is selected from the group consisting of anxietydisorder, depression, bipolar disorder, schizophrenia, and psychosis.18. A compound as claimed in claim 1 which is:N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamideor a physiologically tolerated salt thereof.
 19. A compound as claimedin claim 1 which is:N-[2-(3-benzyl-2-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-pyrazole-4-sulfonamideor a physiologically tolerated salt thereof.
 20. A compound as claimedin claim 1 which is:N-[2-(3-benzyl-3-methyl-isoindolin-5-yl)oxyethyl]-1-methyl-imidazole-4-sulfonamideor a physiologically tolerated salt thereof.